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DNA repair systems in malignant mesothelioma
Cancer Letters 312 (2011) 143–149
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Cancer Letters journal homepage: www.elsevier.com/locate/canlet
Mini-review
DNA repair systems in malignant mesothelioma Dimitrios Toumpanakis, Stamatios E. Theocharis ⇑ Department of Forensic Medicine and Toxicology, National and Kapodistrian University of Athens, Medical School, Goudi 11527, Athens, Greece
a r t i c l e
i n f o
Article history: Received 8 June 2011 Received in revised form 19 August 2011 Accepted 21 August 2011
Keywords: Malignant mesothelioma Asbestos DNA repair Gene expression Polymorphisms
a b s t r a c t Malignant mesothelioma (MM) is an aggressive tumor of serosal surfaces with increasing incidence and poor prognosis. Asbestos exposure is the main cause of MM and asbestosinduced DNA damage is critical for MM pathogenesis. The present review summarizes the implications of DNA repair systems in MM development, focusing on gene expression alterations and single nucleotide polymorphisms of genes encoding for DNA repair enzymes. The involvement of DNA repair systems in MM improves understanding of MM pathogenesis and provides novel therapeutical targets. Ó 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Malignant mesothelioma (MM) is a tumor originating from mesothelial cells of serosal surfaces, mainly the pleura and the peritoneum. MM is an aggressive tumor, characterized by treatment resistance and poor prognosis. Abbreviations: APE, apurinic/apyrimidinic endonuclease; ATM, ataxia telengiectasia mutated; ATR, ataxia telengiectasia related; BER, base excision repair; BRCA, breast cancer; CIs, confidence intervals; DNA-PKcs, DNA dependent protein kinase catalytic subunit; DSB, double-strand break; ERCC, excision repair cross-complementing; FANC, fanconi anemia complementation; FEN1, flap endonuclease 1; GG-NER, global genome nucleotide excision repair; HR, homologous recombination; MLH, human MutL homolog; MSH, human MutS homolog; MTH, human MuT homolog; MYH, human MutY homolog; 8-OHdG, 8-hydroxydeoxyguanosine; MM, malignant mesothelioma; O6-MGMT, O6-methylguanine methyltransferase; MMR, mismatch repair; NHEJ, nonhomologous end-joining; NER, nucleotide excision repair; OR, odds ratio; ARF, open reading frame; Ogg1, 8-oxoguanine DNA glycosylase 1; PARP, poly(ADP-ribose) polymerase; PCNA, proliferating cell nuclear antigen; RNS, reactive nitrogen species; ROS, reactive oxygen species; RPA, replication factor A; SNP, single nucleotide polymorphism; SSB, single-strand break; TC-NER, transcription coupled nucleotide excision repair; TFIIH, transcription factor IIH; TLS, translesion synthesis; Ung2, uracil-DNA glycosylase 2; XP, xeroderma pigmentosum; XRCC, X-ray cross complementing. ⇑ Corresponding author. Address: Department of Forensic Medicine and Toxicology, National and Kapodistrian University of Athens, Medical School, 75 Mikras Asias Street, Goudi 11527, Athens, Greece. E-mail address: [email protected] (S.E. Theocharis). 0304-3835/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2011.08.021
Although rare in the past, MMs incidence is increasing. Asbestos exposure is the main cause of MM with malignancy development following a latent period reaching up to 30 years from first exposure [1–3]. The mechanisms by which asbestos exposure results in malignant mesothelioma are (a) chronic irritation of pleura by asbestos fibers, (b) interference of the fibers with the mitotic machinery leading to chromosomal damage, (c) activation of cellular pathways, including the mitogenactivated protein kinase signaling and Nuclear Factor kB pathway and (d) generation of oxidative stress with subsequent DNA damage [1,4]. Reactive oxygen species (ROS) are produced by asbestos fibers both by reactions at fiber surfaces, by a process requiring iron molecules or by phagocytosis of asbestos fibers by mesothelial cells or sequestrated macrophages. Asbestos fibers have been also found to produce reactive nitrogen species (RNS) [5]. Moreover both ROS and RNS could be generated during the inflammatory process initiated by asbestos exposure [6]. DNA repair enzymes are critical for the maintenance of genome [7] and defects in repair process create a ‘‘mutator phenotype’’ leading to genome instability and promoting tumorigenesis [8,9]. On the other hand, adequate DNA repair provides resistance to therapeutic radiation and some cytotoxic chemotherapy [10]. Moreover, combined
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impairment in different DNA repair systems leads to gross genomic instability and death of tumor cells, a principle called ‘‘synthetic lethality’’ [11,12]. Thus, DNA repair systems play a pivotal role in carcinogenesis and are potential targets for cancer therapy [13]. The aim of the present review is to summarize the implications of the DNA repair systems to malignant mesothelioma pathogenesis with possible treatment options. A short overview of DNA repair enzymes is primarily given. 2. DNA damage repair systems and theirs implications in malignant mesothelioma In mammals, four DNA damage repair systems are recognized responsible for repairing different DNA lesions, but also with overlapping characteristics; base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR) and recombinational system repair [homologous recombination (HR) and nonhomologous end-joining (NHEJ)] [7,14,15]. 2.1. Base excision repair BER mainly corrects lesions produced by oxidative stress, alkylation, methylation, hydroxylation or deamination that provoke small base alterations without distorting the DNA helix [7,16,17]. Initially, the damaged base is recognized and removed by a lesion-specific DNA glycosylase. Following the removal of the base, the apurinic/apyrimidinic endonuclease 1 (APE1) is recruited at the abasic site of the DNA helix and produces a strand incision. The remaining process can follow two alternatives, i.e. the short patch BER and the long patch [7]. In the short patch pathway a single base replacement is performed by DNA polymerase b (polb) and DNA ligase3. The X-ray cross complementing group 1 (XRCC1) protein contributes also to short patch BER, acting as a scaffold protein binding to various other proteins including DNA polb and DNA ligase3. In the long patch pathway, DNA synthesis of multiple nucleotides (2–10 bases) occurs by the action of DNA pold/e, proliferating cell nuclear antigen (PCNA), the flap endonuclease 1 (FEN1) and DNA ligase1. Interestingly, BER components are also used to repair single-stranded DNA breaks (SSB) [7,18]. XRCC1 and poly(ADP-ribose) polymerase (PARP) serve as SSB sensors. The lesion is then repaired by BER components (short or long patch) [14]. 2.2. Malignant mesothelioma and base excision repair As previously mentioned, BER represents the major repair system for DNA damage caused by oxidative stress. Asbestos exposure is characterized by the induction of ROS resulting in DNA damage. A frequent lesion following asbestos exposure is the formation of 8-hydroxydeoxyguanosine (8-OHdG) [19,20]. Indeed, increased levels of 8-OHdG were found in the culture media of in vitro crocidolite asbestos exposed human mesothelial cells (MET5A cell line) [21] and in the peritoneum of rats treated in vivo with asbestos [22]. This lesion is highly mutagenic, since 8-OHdG pairs during replication with both C and A, resulting in G/T
transversions. When paired with C, 8-OHdG is repaired by the short-patch BER with the contribution of 8-oxoguanine DNA glycosylase 1 (Ogg1). Instead, 8-OHdG/A mispairs are repaired by long patch BER [initiated by the action of human homolog of Escherichia coli MutY (MYH) glycosylase]. Additional repair mechanisms for 8-OHdG are MMR that prevent 8-OHdG from pairing to A during genome replication and the human homolog of E. coli MuT (MTH) enzyme that repairs 8-OHdG nucleotide prior to inserting to DNA [23]. Other DNA lesion occurring in mesothelioma and repaired from BER elements are single strand breaks [20,24]. As noted before XRCC1 is a member of the core proteins of BER system contributing also to SSB repair. In asbestosexposed subjects, increased risk of MM was noted for the single nucleotide polymorphism (SNP) XRCC1-399Q that substitutes Arg to Gln in position 399 [odds ratio (OR) = 2.15; confidence intervals (CIs) = 1.08–4.28] [25]. This polymorphism lies in the region of the XRCC1 molecule, responsible for interaction with the protein PCNA and repair of SSB [26], but substitution of Arg to Gln could also affect the connection of XRCC1 with other members of the BER family including glycosylases [27]. Although in an in vitro study this SNP did not show defects for DNA repair [28], the 399Q allele has been associated with increased DNA damage in vivo and multiple human cancers [29]. In accordance with the aforementioned study, the SNP XRCC1-399Q was also shown to correlate with MM in a recent study for asbestos exposed subjects [30]. In contrast, no correlation was found between XRCC1-399Q and MM when this was assessed independent of asbestos exposure [31]. Other proteins of the BER system have been also implicated in MM pathogenesis. Increased expression and activity of APE was noted in rat pleural mesothelial cells secondary to crocidolite asbestos exposure in vitro [32]. Two studies have searched the correlation of the D148E (rs3136820) SNP of APE to MM but showed no significant results [30,31]. However, a meta-analysis of the two studies revealed a significant correlation of APE D148E with MM (OR 1.72, 95% CIs 1.02–2.91) [30]. It is worth noticing that this SNP has not been found to alter the endonuclease activity of APE [33], although correlated with other human cancers, as well [34]. The implication of Ogg1 in MM development has also been studied. The polymorphism S326C although found in vitro to suppress the action of Ogg1 [35], was not associated in clinical studies with a significant increase in MM [25,30,31]. On the other hand, deletions of 3p chromosome have been reported in MM, the region that Ogg1 gene is located [36,37]. Several other studies have implicated BER family proteins in MM pathophysiology. PARP was upregulated and activated in human mesothelial cells following asbestos exposure [38,39]. Indeed, PARP inhibition resulted in a potentiation in SSB formation following direct asbestos exposure of human mesothelial cells [40]. Interestingly, beside its role in DNA repair [41], PARP has been implicated in induction of apoptosis and cell death following asbestos exposure [19,38,39]. Gene expression analysis has also revealed an overexpression of three genes involved in BER encoding for
D. Toumpanakis, S.E. Theocharis / Cancer Letters 312 (2011) 143–149 Table 1 Altered gene expression of proteins of DNA repair systems reported in malignant mesothelioma. DNA repair system
Genes upregulated
Genes downregulated
Ref.
BER
PCNA, FEN1, Ung2, PARPa p44 MSH6 RAD50, RAD54L, RAD21, BRCA2, FANCA, FANCD2 XRCC4, Ku80a Rad18
Ung2
[38,39,42,44]
– – –
[42] [42] [42]
– –
[42,71] [42]
NER MMR HR
NHEJ TLS a
Data from in vitro studies.
Table 2 Polymorphisms of genes encoding proteins of DNA repair systems associated with risk for malignant mesothelioma. DNA repair system
Gene
Polymorphism
Correlation with MM
Ref.
BER
XRCC1
rs25487, Arg399Gln
Increased risk between asbestos exposed subjects for the Gln allele Increased risk for MM for Glu homozygotes Increased risk for MM for CT heterozygotes Increased DNA damage for the A allele between mineral fiber exposed workers Increased methylation of MGMT promoter with T allele
[25,30]
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group C (XPC) protein recognizes DNA helix distorting lesions throughout the genome. Following, both the complex transcription factor IIH (TFIIH) with helicase activity and the endonuclease XPG are recruited to the lesion. In TC-NER, the DNA repair is initiated when a DNA lesion causes RNA polymerase II to stall during transcription. This leads to recruitment of various proteins, including the transcription factor TFIIH and XPG endonuclease [46,47]. The remaining repair process is common for both subpathways [7,14,45,48]. Initially, the proteins XPA and replication factor A (RPA) are recruited, responsible for confirming the presence of DNA damage and stabilizing the open bubble structures of the DNA helices (accomplished by the action of the helicases XPB and XPD, units of the factor TFIIH), respectively. Following, the dimer Excision repair cross-complementing group 1 (ERCC1)–XPG with endonuclease activity is recruited. An oligonucleotide around the DNA lesion (24–32 bases) is cleaved by the action of XPG and ERCC1 and the classical DNA replication machinery completes DNA repair. Interestingly, XPA contributes to ERCC1 recruitment and activation of XPG endonuclease [46]. 2.4. Malignant mesothelioma and nucleotide excision repair
BER
APE
rs313682, Asp148Glu
NER
ERCC1
NER
XPA
rs11615, Asn118Asn (C/T) rs1800975, A23G (noncoding region)
Direct repair
MGMT
rs16906252, C-56T (noncoding region)
[30]
[30]
[52]
[78]
proteins PCNA, FEN1 and the uracil-DNA glycosylase 2 (Ung2) [42] (an uracil glycosylase repairing misincorporation of uracil or deamination of cytosine [43]). In contrast, Singhal et al. reported downregulation of Ung2 gene in MM [44]. (A summary of DNA repair gene expression in MM is presented in Table 1.). Recent studies have also assessed possible associations of MM risk with SNPs for the proteins of the BER family, PCNA, PARP, ligase1, hMYH and polb, without producing significant correlations [30,31]. (For a summary of SNPs associated with MM see Table 2.) 2.3. Nucleotide excision repair NER is a crucial repair system against helix distorting DNA lesions, including those produced by anti-cancer agents [7,10]. NER is divided into two subpathways depending on the mechanism by which DNA damage is recognized; the global genome nucleotide excision repair (GG-NER) and transcription coupled repair (TC-NER) [45]. In GG-NER, a protein complex containing the Xeroderma Pigmentosum
Various studies have searched the implication of proteins of the NER family in MM development. A significant correlation of the SNP N118N (C > T) of ERCC1 with MM has been reported (heterozygotes OR = 1.59, CIs = 1.01– 2.50) [30]. Since ERCC1 contributes also to repair of interstrand links [49], this polymorphism could play a role in resistance to cisplatin therapy. Although, in vitro this SNP did not alter ERCC1 expression or platinum sensitivity [50], it was associated with response to cisplatin treatment in patients with non-small cell lung cancer [51]. In workers exposed to mineral fibers, including asbestos, increased DNA damage was noticed associated with the presence of adenosine (A) nucleotide in the SNP A23G of XPA gene [52]. This polymorphism lies on the 50 untranslated region of XPA gene but its effect on XPA expression and function is not known. The G allele has been correlated with increased DNA repair capacity [53] and reduced risk for lung cancer [53,54]. Gene expression study in patients with MM also revealed an up-regulation of the p44 gene expression that encodes a subunit of TFIIH core [42]. SNPs in the genes of XPD and XPG have been also studied for possible correlations with MM risk without raising however significant results [25,30,31]. 2.5. Mismatch repair system MMR system corrects mispaired nucleotides formed by replication errors, as well as insertion/deletion loops that arise from strand slippage during replication of repetitive sequences [7]. Proteins of the MMR system in human are referred to as homologs of the E. coli MMR system and include proteins MSH2, MSH3, MSH6 (homologs of MutS), proteins MLH1, MLH3, PMS1, PMS2 (homologs of MutL), while homologs for MutH have not been yet identified [55]. The heterodimer MSH2/6 (MutSa) recognizes mismatches and small DNA loops, while the dimer MSH2/3
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(MSHb) bind to larger insertion/deletion loops [7,56]. Following DNA strand discrimination, MutL homologs form heterodimers that interact with MutS and various downstream proteins [55]. Excision of the strand containing the mismatch and DNA refilling is achieved by various protein components including pold/e, RPA, PCNA and DNA ligase1 [7,55]. 2.6. Malignant mesothelioma and mismatch repair To our knowledge, there is lack of evidence in literature for the implication of MMR in MM. Genome analysis has revealed an upregulation of MSH6 gene expression in MM [42]. Moreover, no significant correlation were found between various SNPs of MLH1, MSH2, MSH3 and MSH6 genes and the risk for MM development [31]. 2.7. Recombination repair system (homologous recombination – end joining) Recombination repair corrects DNA double-strand breaks (DSBs) and interstrand cross links [7]. The sources of DSBs in mammalian cells are among others environmental factors such as ionizing radiation, chemicals (including anti-tumor agents), unrepaired single strand breaks, stalled or collapsed DNA replication forks [45,57]. DSBs are repaired by two systems; HR, where repair is based on connection with the sister chromatid and is error free and NHEJ, which consists of direct break ligation and is error prone [7]. An initial event in DSBs is the recruitment and activation of the ataxia telengiectasia mutated (ATM) and ataxia telengiectasia related (ATR) proteins with multiple downstream substrates participating in cell cycle arrest (through activation of p53) and DNA repair process [including the Mre11-Nbs1-RAD50 (MNR) complex] [58,59]. When homologous recombination is preferred for DNA repair a multi-step process is performed including the exposure of the 30 -OH ends by MNR complex, formation of nucleoprotein filaments (involves the proteins RAD51, XRCC2, XRCC3), strand connection with a homologous sequence, DNA synthesis and resolve of the DNA connections (called Holliday junctions). Many other protein contribute to HR, including RAD52, RAD54, RPA and Breast Cancer 1 and 2 (BRCA1/2) [7,59,60]. In NHEJ, DSBs are recognized by the KU70/80 dimer initiating the repair cascade. Joining of DSBs ends is then performed by the action of the Artemis/DNAdependent protein kinase (DNA-PKcs) complex (with endonuclease activity) and XRCC4-ligase4 complex. Poll and k can fill DNA gaps arising during repair process [61,62]. 2.8. Malignant mesothelioma and homologous recombination As mentioned before, homologous recombination repairs DSBs and interstrand crosslinks. This is of great importance, since DSBs induce major chromosomal lesions, including deletions and translocations and can result in cell death [59]. Asbestos exposure has been found to induce DSBs in mesothelial cells [19,20] and chromosomal deletions are very common in malignant mesothelioma [36,37].
An analysis of gene expression in MM, revealed an upregulation of various genes encoding HR protein members, including proteins RAD50, RAD54L, RAD21 and BRCA2 [42]. On the other hand, loss of heterozygosity has been noted in MM for the regions 15q11.1-15 and 13q12-14 where genes for the RAD51 and BRCA2 locate [63]. Moreover, no SNP of genes encoding for HR protein members (RAD51, RAD52, RAD54, XRCC2, XRCC3, BRCA1 and BRCA2) had a significant correlation for MM development [31]. Although impaired DNA repair could promote mutagenesis, an intact HR repair system may increase resistance to radiotherapy and chemotherapy [10]. Indeed, increased expression of BRCA1 and BRCA2 was found in MM cell lines and treatment with extracellular regulated kinase inhibitors increased sensitivity to doxorubicin, through many mechanisms including defect DNA repair by lowering BRCA2 levels [64]. Interestingly, members of the Fanconi Anemia (FA) protein family were also upregulated in MM, including Fanconi Anemia complementation group A and D2 (FANCA and FANCD2) [42]. When activated by DNA damage, the FA pathway leads to mono-ubiquitylation of FANCD2 that interacts with others proteins, including ATM, BRCA1 and BRCA2 promoting DNA repair by homologous recombination [65,66]. DNA damage results in activation of p53 and cell cycle arrest to allow DNA repair or induces cell apoptosis. Although mutations in p53 gene are common in human cancers, no point mutations has been found in MM [67]. Moreover, expression of p53 is usually normal in mesothelioma [42] and various SNPs of the p53 gene were not associated with the risk for MM [31]. However, infection with virus SV40, a potential co-factor for MM [2], results in p53 inactivation through interaction of p53 with the protein Tag encoded by the virus DNA [68]. Inactivation of p53 in MM could also result from down-regulation of its activator open reading frame protein (p14/ARF), since the gene encoding p14/ARF is located in the 19p21-22 region that is frequently deleted in MM [36,69]. Indeed, transgenic mice with deletions of p14/ARF gene showed increased incidence and shorter latency time for MM development following asbestos exposure [70]. 2.9. Malignant mesothelioma and nonhomologous end joining The implication of various members of the NHEJ repair family in MM has been reported. Overexpression of the gene encoding for the protein Ku80 has been found in mesothelioma cell lines [71]. In another study, SNPs of the gene were not associated with the risk for MM [31]. Interestingly, XRCC4, a key gene of NHEJ, is also upregulated in MM [42]. Since NHEJ repairs DSBs that are also formed during anti-cancer therapy (e.g. by ionizing radiation and topoisomerases inhibitors) [10], the implication of NHEJ in MM could provide novel therapeutical targets. On the other hand, a point mutation of the gene encoding the protein Ku70 has been detected in a patient with pleural MM that results in V296M amino acid substitution in the region that contacts Ku80 [72]. Defective action of the Ku70/Ku80 dimer could impair DNA repair and promote mutagenesis.
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2.10. Additional mechanisms of DNA repair Further DNA repair enzymes are single proteins that revert directly the DNA lesion, including O6-methylguanine methyltransferase (O6-MGMT) that removes methyl groups from O6 position of guanine, a highly mutagenic DNA lesion that results in G/C to A/T conversion [7,73]. In addition to DNA repair systems, the cells employ mechanisms to bypass DNA lesions during replication, a process called ‘‘translesion synthesis’’ (TLS). This consists of replacing regular DNA polymerases when a damaged site is encountered, by translesion polymerases (polf-j) that replicate DNA with lesser base-pairing requirements (with the action of additional factors) [11,74]. 2.11. Malignant mesothelioma and direct repair of DNA lesions MGMT gene expression is under epigenetic control and suppressed by methylation of its promoter in CpG islands [75]. Methylation of the promoter of MGMT gene is common in human cancer [76]. Moreover, since alkylation of O6 sites is among the mechanisms of the alkylating chemotherapeutic drugs, depressed MGMT activity could enhance their therapeutic action [73]. DNA methylation is found in various loci in MM [77]. Kristensen et al. studied biopsies from 95 patients with pleural MM and detected methylation of the promoter of MGMT gene in 13 of them [78]. Interestingly, methylation status was correlated with the T allele of the rs16906252 polymorphism, in accordance with studies on colorectal cancer [79]. However, gene silencing was a rare event, limiting MGMT value in MM pathogenesis [78]. 2.12. Malignant mesothelioma and translesion synthesis An important step of the bypass replication during TLS is the mono-ubiquitylation of PCNA mediated by Rad6/ Rad18 [80]. Rad18 has been found to be upregulated in MM [42]. Since translesion synthesis is implicated in repair of interstrand crosslinks, the upregulation of Rad18 could possible contribute to resistance to anti-cancer agents, including cisplatin and mitomycin C [81]. It is worth mentioning that PCNA is a protein with multiple functions in DNA replication and repair, including BER, NER, MMR and translesion synthesis [82]. Although, immunohistological detection of PCNA is not included in current European guidelines for management of pleural MM [3], PCNA has been reported to discriminate between MM and mesothelial hyperplasia and to possess prognostic value [83,84]. 3. Conclusion In conclusion, as presented in this review, several studies have provided accumulating data for the implication of DNA repair mechanisms in MM pathogenesis. Defective repair mechanisms caused by either lowered gene expression or single nucleotide polymorphisms (Table 2) that affect enzyme function, can augment mutagenesis and act synergistically to asbestos exposure. The latter raises also the issue of a more individualized
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approach to disease progression. On the other hand, increased expression (Table 1) and activity of DNA repair enzymes may protect mesothelial cells from asbestosinduced DNA damage but augments resistance to chemoand radiotherapy of MM tumor cells. Thus, blocking the activated DNA repair enzymes or extending DNA repair deficiency in tumors already presenting DNA repair defects could provide novel targets for the treatment of MM as single therapy or in combination with standard anti-cancer therapy.
References [1] B.W. Robinson, R.A. Lake, Advances in malignant mesothelioma, New Engl. J. Med. 353 (2005) 1591–1603. [2] B.W. Robinson, A.W. Musk, R.A. Lake, Malignant mesothelioma, Lancet 366 (2005) 397–408. [3] A. Scherpereel, P. Astoul, P. Baas, T. Berghmans, H. Clayson, P. de Vuyst, H. Dienemann, F. Galateau-Salle, C. Hennequin, G. Hillerdal, C. Le Pechoux, L. Mutti, J.C. Pairon, R. Stahel, P. van Houtte, J. van Meerbeeck, D. Waller, W. Weder, Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma, Eur. Respir. J. 35 (2010) 479–495. [4] N.H. Heintz, Y.M. Janssen-Heininger, B.T. Mossman, Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways, Am. J. Respir. Cell Mol. Biol. 42 (2010) 133–139. [5] N. Choe, S. Tanaka, E. Kagan, Asbestos fibers and interleukin-1 upregulate the formation of reactive nitrogen species in rat pleural mesothelial cells, Am. J. Respir. Cell Mol. Biol. 19 (1998) 226–236. [6] S.P. Hussain, C.C. Harris, Inflammation and cancer: an ancient link with novel potentials, Int. J. Cancer 121 (2007) 2373–2380. [7] J.H. Hoeijmakers, Genome maintenance mechanisms for preventing cancer, Nature 411 (2001) 366–374. [8] L.A. Loeb, K.R. Loeb, J.P. Anderson, Multiple mutations and cancer, Proc. Natl Acad. Sci. USA 100 (2003) 776–781. [9] M.R. Stratton, P.J. Campbell, P.A. Futreal, The cancer genome, Nature 458 (2009) 719–724. [10] T. Helleday, E. Petermann, C. Lundin, B. Hodgson, R.A. Sharma, DNA repair pathways as targets for cancer therapy, Nat. Rev. Cancer 8 (2008) 193–204. [11] S.P. Jackson, J. Bartek, The DNA-damage response in human biology and disease, Nature 461 (2009) 1071–1078. [12] H. Farmer, N. McCabe, C.J. Lord, A.N. Tutt, D.A. Johnson, T.B. Richardson, M. Santarosa, K.J. Dillon, I. Hickson, C. Knights, N.M. Martin, S.P. Jackson, G.C. Smith, A. Ashworth, Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, Nature 434 (2005) 917–921. [13] S.A. Martin, C.J. Lord, A. Ashworth, DNA repair deficiency as a therapeutic target in cancer, Curr. Opin. Genet. Dev. 18 (2008) 80– 86. [14] T. Lindahl, R.D. Wood, Quality control by DNA repair, Science 286 (1999) 1897–1905. [15] E. Gatzidou, C. Michailidi, S. Tseleni-Balafouta, S. Theocharis, An epitome of DNA repair related genes and mechanisms in thyroid carcinoma, Cancer Lett. 290 (2010) 139–147. [16] T. Lindahl, Suppression of spontaneous mutagenesis in human cells by DNA base excision-repair, Mutat. Res. 462 (2000) 129–135. [17] H.E. Krokan, H. Nilsen, F. Skorpen, M. Otterlei, G. Slupphaug, Base excision repair of DNA in mammalian cells, FEBS Lett. 476 (2000) 73–77. [18] M.L. Hegde, T.K. Hazra, S. Mitra, Early steps in the DNA base excision/ single-strand interruption repair pathway in mammalian cells, Cell Res. 18 (2008) 27–47. [19] D. Upadhyay, D.W. Kamp, Asbestos-induced pulmonary toxicity: role of DNA damage and apoptosis, Exp. Biol. Med. (Maywood.) 228 (2003) 650–659. [20] M.C. Jaurand, Mechanisms of fiber-induced genotoxicity, Environ. Health Perspect. 105 (Suppl. 5) (1997) 1073–1084. [21] Q. Chen, J. Marsh, B. Ames, B. Mossman, Detection of 8-oxo-20 deoxyguanosine, a marker of oxidative DNA damage, in culture medium from human mesothelial cells exposed to crocidolite asbestos, Carcinogenesis 17 (1996) 2525–2527.
148
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[22] K. Unfried, C. Schurkes, J. Abel, Distinct spectrum of mutations induced by crocidolite asbestos: clue for 8-hydroxydeoxyguanosinedependent mutagenesis in vivo, Cancer Res. 62 (2002) 99–104. [23] P. Fortini, B. Pascucci, E. Parlanti, M. D’Errico, V. Simonelli, E. Dogliotti, 8-Oxoguanine DNA damage: at the crossroad of alternative repair pathways, Mutat. Res. 531 (2003) 127–139. [24] T. Ollikainen, K. Linnainmaa, V.L. Kinnula, DNA single strand breaks induced by asbestos fibers in human pleural mesothelial cells in vitro, Environ. Mol. Mutagen. 33 (1999) 153–160. [25] I. Dianzani, L. Gibello, A. Biava, M. Giordano, M. Bertolotti, M. Betti, D. Ferrante, S. Guarrera, G.P. Betta, D. Mirabelli, G. Matullo, C. Magnani, Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study, Mutat. Res. 599 (2006) 124–134. [26] K.W. Caldecott, XRCC1 and DNA strand break repair, DNA Repair (Amst) 2 (2003) 955–969. [27] R. Monaco, R. Rosal, M.A. Dolan, M.R. Pincus, P.W. Brandt-Rauf, Conformational effects of a common codon 399 polymorphism on the BRCT1 domain of the XRCC1 protein, Protein J. 26 (2007) 541– 546. [28] R.M. Taylor, A. Thistlethwaite, K.W. Caldecott, Central role for the XRCC1 BRCT I domain in mammalian DNA single-strand break repair, Mol. Cell. Biol. 22 (2002) 2556–2563. [29] W. Ladiges, J. Wiley, A. MacAuley, Polymorphisms in the DNA repair gene XRCC1 and age-related disease, Mech. Ageing Dev. 124 (2003) 27–32. [30] M. Betti, D. Ferrante, M. Padoan, S. Guarrera, M. Giordano, A. Aspesi, D. Mirabelli, C. Casadio, F. Ardissone, E. Ruffini, P.G. Betta, R. Libener, R. Guaschino, G. Matullo, E. Piccolini, C. Magnani, I. Dianzani, XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a casecontrol study, Mutat. Res. 708 (2011) 11–20. [31] F. Gemignani, M. Neri, F. Bottari, R. Barale, P.A. Canessa, F. Canzian, M. Ceppi, I. Spitaleri, M. Cipollini, G.P. Ivaldi, M. Mencoboni, P. Scaruffi, G.P. Tonini, D. Ugolini, L. Mutti, S. Bonassi, S. Landi, Risk of malignant pleural mesothelioma and polymorphisms in genes involved in the genome stability and xenobiotics metabolism, Mutat. Res. 671 (2009) 76–83. [32] H. Fung, Y.W. Kow, B. Van Houten, D.J. Taatjes, Z. Hatahet, Y.M. Janssen, P. Vacek, S.P. Faux, B.T. Mossman, Asbestos increases mammalian AP-endonuclease gene expression, protein levels, and enzyme activity in mesothelial cells, Cancer Res. 58 (1998) 189–194. [33] S. Daviet, S. Couve-Privat, L. Gros, K. Shinozuka, H. Ide, M. Saparbaev, A.A. Ishchenko, Major oxidative products of cytosine are substrates for the nucleotide incision repair pathway, DNA Repair (Amst) 6 (2007) 8–18. [34] J.J. Hu, T.R. Smith, M.S. Miller, K. Lohman, L.D. Case, Genetic regulation of ionizing radiation sensitivity and breast cancer risk, Environ. Mol. Mutagen. 39 (2002) 208–215. [35] A. Yamane, T. Kohno, K. Ito, N. Sunaga, K. Aoki, K. Yoshimura, H. Murakami, Y. Nojima, J. Yokota, Differential ability of polymorphic OGG1 proteins to suppress mutagenesis induced by 8hydroxyguanine in human cell in vivo, Carcinogenesis 25 (2004) 1689–1694. [36] T. Taguchi, S.C. Jhanwar, J.M. Siegfried, S.M. Keller, J.R. Testa, Recurrent deletions of specific chromosomal sites in 1p, 3p, 6q, and 9p in human malignant mesothelioma, Cancer Res. 53 (1993) 4349–4355. [37] S. Neragi-Miandoab, D.J. Sugarbaker, Chromosomal deletion in patients with malignant pleural mesothelioma, Interact. Cardiovasc. Thorac. Surg. 9 (2009) 42–44. [38] H. Yang, Z. Rivera, S. Jube, M. Nasu, P. Bertino, C. Goparaju, G. Franzoso, M.T. Lotze, T. Krausz, H.I. Pass, M.E. Bianchi, M. Carbone, Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation, Proc. Natl. Acad. Sci. USA 107 (2010) 12611–12616. [39] V.C. Broaddus, L. Yang, L.M. Scavo, J.D. Ernst, A.M. Boylan, Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species, J. Clin. Invest. 98 (1996) 2050–2059. [40] T. Ollikainen, A. Puhakka, K. Kahlos, K. Linnainmaa, V.L. Kinnula, Modulation of cell and DNA damage by poly(ADP)ribose polymerase in lung cells exposed to H(2)O(2) or asbestos fibres, Mutat. Res. 470 (2000) 77–84. [41] H.Y. Dong, A. Buard, F. Levy, A. Renier, F. Laval, M.C. Jaurand, Synthesis of poly(ADP-ribose) in asbestos treated rat pleural mesothelial cells in culture, Mutat. Res. 331 (1995) 197–204. [42] O.D. Roe, E. Anderssen, H. Sandeck, T. Christensen, E. Larsson, S. Lundgren, Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets, Lung Cancer 67 (2010) 57–68.
[43] H.E. Krokan, R. Standal, G. Slupphaug, DNA glycosylases in the base excision repair of DNA, Biochem. J. 325 (Pt. 1) (1997) 1–16. [44] S. Singhal, R. Wiewrodt, L.D. Malden, K.M. Amin, K. Matzie, J. Friedberg, J.C. Kucharczuk, L.A. Litzky, S.W. Johnson, L.R. Kaiser, S.M. Albelda, Gene expression profiling of malignant mesothelioma, Clin. Cancer Res. 9 (2003) 3080–3097. [45] C.L. Peterson, J. Cote, Cellular machineries for chromosomal DNA repair, Genes Dev. 18 (2004) 602–616. [46] M. Volker, M.J. Mone, P. Karmakar, A. van Hoffen, W. Schul, W. Vermeulen, J.H. Hoeijmakers, R. van Driel, A.A. van Zeeland, L.H. Mullenders, Sequential assembly of the nucleotide excision repair factors in vivo, Mol. Cell 8 (2001) 213–224. [47] R. Dip, U. Camenisch, H. Naegeli, Mechanisms of DNA damage recognition and strand discrimination in human nucleotide excision repair, DNA Repair (Amst) 3 (2004) 1409–1423. [48] J.R. Mitchell, J.H. Hoeijmakers, L.J. Niedernhofer, Divide and conquer: nucleotide excision repair battles cancer and ageing, Curr. Opin. Cell Biol. 15 (2003) 232–240. [49] D.T. Bergstralh, J. Sekelsky, Interstrand crosslink repair: can XPFERCC1 be let off the hook?, Trends Genet 24 (2008) 70–76. [50] R. Gao, K. Reece, T. Sissung, E. Reed, D.K. Price, W.D. Figg, The ERCC1 N118N polymorphism does not change cellular ERCC1 protein expression or platinum sensitivity, Mutat. Res. 708 (2011) 21–27. [51] A. Kalikaki, M. Kanaki, H. Vassalou, J. Souglakos, A. Voutsina, V. Georgoulias, D. Mavroudis, DNA repair gene polymorphisms predict favorable clinical outcome in advanced non-small-cell lung cancer, Clin. Lung Cancer 10 (2009) 118–123. [52] M. Dusinska, Z. Dzupinkova, L. Wsolova, V. Harrington, A.R. Collins, Possible involvement of XPA in repair of oxidative DNA damage deduced from analysis of damage, repair and genotype in a human population stud, Mutagenesis 21 (2006) 205–211. [53] X. Wu, H. Zhao, Q. Wei, C.I. Amos, K. Zhang, Z. Guo, Y. Qiao, W.K. Hong, M.R. Spitz, XPA polymorphism associated with reduced lung cancer risk and a modulating effect on nucleotide excision repair capacity, Carcinogenesis 24 (2003) 505–509. [54] J.Y. Park, S.H. Park, J.E. Choi, S.Y. Lee, H.S. Jeon, S.I. Cha, C.H. Kim, J.H. Park, S. Kam, R.W. Park, I.S. Kim, T.H. Jung, Polymorphisms of the DNA repair gene xeroderma pigmentosum group A and risk of primary lung cancer, Cancer Epidemiol. Biomarkers Prev. 11 (2002) 993–997. [55] G.M. Li, Mechanisms and functions of DNA mismatch repair, Cell Res. 18 (2008) 85–98. [56] B.D. Harfe, S. Jinks-Robertson, DNA mismatch repair and genetic instability, Annu. Rev. Genet. 34 (2000) 359–399. [57] K.K. Khanna, S.P. Jackson, DNA double-strand breaks: signaling, repair and the cancer connection, Nat. Genet. 27 (2001) 247–254. [58] L.H. Thompson, D. Schild, Recombinational DNA repair and human disease, Mutat. Res. 509 (2002) 49–78. [59] M. Shrivastav, L.P. De Haro, J.A. Nickoloff, Regulation of DNA doublestrand break repair pathway choice, Cell Res. 18 (2008) 134–147. [60] J. San Filippo, P. Sung, H. Klein, Mechanism of eukaryotic homologous recombination, Annu. Rev. Biochem. 77 (2008) 229–257. [61] M.R. Lieber, The mechanism of human nonhomologous DNA end joining, J. Biol. Chem. 283 (2008) 1–5. [62] M.R. Lieber, The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway, Annu. Rev. Biochem. 79 (2010) 181–211. [63] B.R. Balsara, D.W. Bell, G. Sonoda, A. De Rienzo, M.S. Du, S.C. Jhanwar, J.R. Testa, Comparative genomic hybridization and loss of heterozygosity analyses identify a common region of deletion at 15q11.1-15 in human malignant mesothelioma, Cancer Res. 59 (1999) 450–454. [64] A. Shukla, J.M. Hillegass, M.B. MacPherson, S.L. Beuschel, P.M. Vacek, H.I. Pass, M. Carbone, J.R. Testa, B.T. Mossman, Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin, Mol. Cancer 9 (2010) 314. [65] K.J. Patel, H. Joenje, Fanconi anemia and DNA replication repair, DNA Repair (Amst) 6 (2007) 885–890. [66] A.D. D’Andrea, M. Grompe, The Fanconi anaemia/BRCA pathway, Nat. Rev. Cancer 3 (2003) 23–34. [67] O. Mor, P. Yaron, M. Huszar, A. Yellin, O. Jakobovitz, F. Brok-Simoni, G. Rechavi, N. Reichert, Absence of p53 mutations in malignant mesotheliomas, Am. J. Respir. Cell Mol. Biol. 16 (1997) 9–13. [68] J.R. Testa, A. Giordano, SV40 and cell cycle perturbations in malignant mesothelioma, Semin. Cancer Biol. 11 (2001) 31–38. [69] J.Q. Cheng, S.C. Jhanwar, W.M. Klein, D.W. Bell, W.C. Lee, D.A. Altomare, T. Nobori, O.I. Olopade, A.J. Buckler, J.R. Testa, P16 alterations and deletion mapping of 9p21–p22 in malignant mesothelioma, Cancer Res. 54 (1994) 5547–5551.
D. Toumpanakis, S.E. Theocharis / Cancer Letters 312 (2011) 143–149 [70] D.A. Altomare, C.W. Menges, J. Xu, J. Pei, L. Zhang, A. Tadevosyan, E. Neumann-Domer, Z. Liu, M. Carbone, I. Chudoba, A.J. KleinSzanto, J.R. Testa, Losses of both products of the cdkn2a/arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis, PLoS ONE 6 (2011) e18828. [71] E. Kettunen, A.M. Nissen, T. Ollikainen, M. Taavitsainen, J. Tapper, K. Mattson, K. Linnainmaa, S. Knuutila, W. El Rifai, Gene expression profiling of malignant mesothelioma cell lines: cDNA array study, Int. J. Cancer 91 (2001) 492–496. [72] D.J. Sugarbaker, W.G. Richards, G.J. Gordon, L. Dong, A. De Rienzo, G. Maulik, J.N. Glickman, L.R. Chirieac, M.L. Hartman, B.E. Taillon, L. Du, P. Bouffard, S.F. Kingsmore, N.A. Miller, A.D. Farmer, R.V. Jensen, S.R. Gullans, R. Bueno, Transcriptome sequencing of malignant pleural mesothelioma tumors, Proc. Natl. Acad. Sci. USA 105 (2008) 3521– 3526. [73] M. Esteller, J.G. Herman, Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer, Oncogene 23 (2004) 1–8. [74] A.R. Lehmann, Replication of damaged DNA by translesion synthesis in human cells, FEBS Lett. 579 (2005) 873–876. [75] G.S. Watts, R.O. Pieper, J.F. Costello, Y.M. Peng, W.S. Dalton, B.W. Futscher, Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene, Mol. Cell. Biol. 17 (1997) 5612–5619. [76] M. Esteller, S.R. Hamilton, P.C. Burger, S.B. Baylin, J.G. Herman, Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia, Cancer Res. 59 (1999) 793– 797. [77] J.A. Tsou, J.S. Galler, A. Wali, W. Ye, K.D. Siegmund, S. Groshen, P.W. Laird, S. Turla, M.N. Koss, H.I. Pass, I.A. Laird-Offringa, DNA
[78]
[79]
[80]
[81]
[82] [83]
[84]
149
methylation profile of 28 potential marker loci in malignant mesothelioma, Lung Cancer 58 (2007) 220–230. L.S. Kristensen, H.M. Nielsen, H. Hager, L.L. Hansen, Methylation of MGMT in malignant pleural mesothelioma occurs in a subset of patients and is associated with the T allele of the rs16906252 MGMT promoter SNP, Lung Cancer 71 (2011) 130–136. S. Ogino, A. Hazra, G.J. Tranah, G.J. Kirkner, T. Kawasaki, K. Nosho, M. Ohnishi, Y. Suemoto, J.A. Meyerhardt, D.J. Hunter, C.S. Fuchs, MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer, Carcinogenesis 28 (2007) 1985–1990. M. Shaheen, I. Shanmugam, R. Hromas, The role of PCNA posttranslational modifications in translesion synthesis, J. Nucleic Acids 2010 (2010). K. Nojima, H. Hochegger, A. Saberi, T. Fukushima, K. Kikuchi, M. Yoshimura, B.J. Orelli, D.K. Bishop, S. Hirano, M. Ohzeki, M. Ishiai, K. Yamamoto, M. Takata, H. Arakawa, J.M. Buerstedde, M. Yamazoe, T. Kawamoto, K. Araki, J.A. Takahashi, N. Hashimoto, S. Takeda, E. Sonoda, Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells, Cancer Res. 65 (2005) 11704–11711. G.L. Moldovan, B. Pfander, S. Jentsch, PCNA, the maestro of the replication fork, Cell 129 (2007) 665–679. V. Esposito, A. Baldi, A. De Luca, G. Paciocco, A. Groger, G. Sgaramella, P.P. Claudio, G.G. Giordano, F. Baldi, M. Caputi, H. Kaiser, A. Giordano, Role of PCNA in differentiating between malignant mesothelioma and mesothelial hyperplasia: prognostic considerations, Anticancer Res. 17 (1997) 601–604. M. Ramael, W. Jacobs, J. Weyler, J. van Meerbeeck, P. Bialasiewicz, B.J. Van den, C. Buysse, P. Vermeire, E. Van Marck, Proliferation in malignant mesothelioma as determined by mitosis counts and immunoreactivity for proliferating cell nuclear antigen (PCNA), J. Pathol. 172 (1994) 247–253.
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Mini-review
DNA repair systems in malignant mesothelioma Dimitrios Toumpanakis, Stamatios E. Theocharis ⇑ Department of Forensic Medicine and Toxicology, National and Kapodistrian University of Athens, Medical School, Goudi 11527, Athens, Greece
a r t i c l e
i n f o
Article history: Received 8 June 2011 Received in revised form 19 August 2011 Accepted 21 August 2011
Keywords: Malignant mesothelioma Asbestos DNA repair Gene expression Polymorphisms
a b s t r a c t Malignant mesothelioma (MM) is an aggressive tumor of serosal surfaces with increasing incidence and poor prognosis. Asbestos exposure is the main cause of MM and asbestosinduced DNA damage is critical for MM pathogenesis. The present review summarizes the implications of DNA repair systems in MM development, focusing on gene expression alterations and single nucleotide polymorphisms of genes encoding for DNA repair enzymes. The involvement of DNA repair systems in MM improves understanding of MM pathogenesis and provides novel therapeutical targets. Ó 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Malignant mesothelioma (MM) is a tumor originating from mesothelial cells of serosal surfaces, mainly the pleura and the peritoneum. MM is an aggressive tumor, characterized by treatment resistance and poor prognosis. Abbreviations: APE, apurinic/apyrimidinic endonuclease; ATM, ataxia telengiectasia mutated; ATR, ataxia telengiectasia related; BER, base excision repair; BRCA, breast cancer; CIs, confidence intervals; DNA-PKcs, DNA dependent protein kinase catalytic subunit; DSB, double-strand break; ERCC, excision repair cross-complementing; FANC, fanconi anemia complementation; FEN1, flap endonuclease 1; GG-NER, global genome nucleotide excision repair; HR, homologous recombination; MLH, human MutL homolog; MSH, human MutS homolog; MTH, human MuT homolog; MYH, human MutY homolog; 8-OHdG, 8-hydroxydeoxyguanosine; MM, malignant mesothelioma; O6-MGMT, O6-methylguanine methyltransferase; MMR, mismatch repair; NHEJ, nonhomologous end-joining; NER, nucleotide excision repair; OR, odds ratio; ARF, open reading frame; Ogg1, 8-oxoguanine DNA glycosylase 1; PARP, poly(ADP-ribose) polymerase; PCNA, proliferating cell nuclear antigen; RNS, reactive nitrogen species; ROS, reactive oxygen species; RPA, replication factor A; SNP, single nucleotide polymorphism; SSB, single-strand break; TC-NER, transcription coupled nucleotide excision repair; TFIIH, transcription factor IIH; TLS, translesion synthesis; Ung2, uracil-DNA glycosylase 2; XP, xeroderma pigmentosum; XRCC, X-ray cross complementing. ⇑ Corresponding author. Address: Department of Forensic Medicine and Toxicology, National and Kapodistrian University of Athens, Medical School, 75 Mikras Asias Street, Goudi 11527, Athens, Greece. E-mail address: [email protected] (S.E. Theocharis). 0304-3835/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2011.08.021
Although rare in the past, MMs incidence is increasing. Asbestos exposure is the main cause of MM with malignancy development following a latent period reaching up to 30 years from first exposure [1–3]. The mechanisms by which asbestos exposure results in malignant mesothelioma are (a) chronic irritation of pleura by asbestos fibers, (b) interference of the fibers with the mitotic machinery leading to chromosomal damage, (c) activation of cellular pathways, including the mitogenactivated protein kinase signaling and Nuclear Factor kB pathway and (d) generation of oxidative stress with subsequent DNA damage [1,4]. Reactive oxygen species (ROS) are produced by asbestos fibers both by reactions at fiber surfaces, by a process requiring iron molecules or by phagocytosis of asbestos fibers by mesothelial cells or sequestrated macrophages. Asbestos fibers have been also found to produce reactive nitrogen species (RNS) [5]. Moreover both ROS and RNS could be generated during the inflammatory process initiated by asbestos exposure [6]. DNA repair enzymes are critical for the maintenance of genome [7] and defects in repair process create a ‘‘mutator phenotype’’ leading to genome instability and promoting tumorigenesis [8,9]. On the other hand, adequate DNA repair provides resistance to therapeutic radiation and some cytotoxic chemotherapy [10]. Moreover, combined
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impairment in different DNA repair systems leads to gross genomic instability and death of tumor cells, a principle called ‘‘synthetic lethality’’ [11,12]. Thus, DNA repair systems play a pivotal role in carcinogenesis and are potential targets for cancer therapy [13]. The aim of the present review is to summarize the implications of the DNA repair systems to malignant mesothelioma pathogenesis with possible treatment options. A short overview of DNA repair enzymes is primarily given. 2. DNA damage repair systems and theirs implications in malignant mesothelioma In mammals, four DNA damage repair systems are recognized responsible for repairing different DNA lesions, but also with overlapping characteristics; base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR) and recombinational system repair [homologous recombination (HR) and nonhomologous end-joining (NHEJ)] [7,14,15]. 2.1. Base excision repair BER mainly corrects lesions produced by oxidative stress, alkylation, methylation, hydroxylation or deamination that provoke small base alterations without distorting the DNA helix [7,16,17]. Initially, the damaged base is recognized and removed by a lesion-specific DNA glycosylase. Following the removal of the base, the apurinic/apyrimidinic endonuclease 1 (APE1) is recruited at the abasic site of the DNA helix and produces a strand incision. The remaining process can follow two alternatives, i.e. the short patch BER and the long patch [7]. In the short patch pathway a single base replacement is performed by DNA polymerase b (polb) and DNA ligase3. The X-ray cross complementing group 1 (XRCC1) protein contributes also to short patch BER, acting as a scaffold protein binding to various other proteins including DNA polb and DNA ligase3. In the long patch pathway, DNA synthesis of multiple nucleotides (2–10 bases) occurs by the action of DNA pold/e, proliferating cell nuclear antigen (PCNA), the flap endonuclease 1 (FEN1) and DNA ligase1. Interestingly, BER components are also used to repair single-stranded DNA breaks (SSB) [7,18]. XRCC1 and poly(ADP-ribose) polymerase (PARP) serve as SSB sensors. The lesion is then repaired by BER components (short or long patch) [14]. 2.2. Malignant mesothelioma and base excision repair As previously mentioned, BER represents the major repair system for DNA damage caused by oxidative stress. Asbestos exposure is characterized by the induction of ROS resulting in DNA damage. A frequent lesion following asbestos exposure is the formation of 8-hydroxydeoxyguanosine (8-OHdG) [19,20]. Indeed, increased levels of 8-OHdG were found in the culture media of in vitro crocidolite asbestos exposed human mesothelial cells (MET5A cell line) [21] and in the peritoneum of rats treated in vivo with asbestos [22]. This lesion is highly mutagenic, since 8-OHdG pairs during replication with both C and A, resulting in G/T
transversions. When paired with C, 8-OHdG is repaired by the short-patch BER with the contribution of 8-oxoguanine DNA glycosylase 1 (Ogg1). Instead, 8-OHdG/A mispairs are repaired by long patch BER [initiated by the action of human homolog of Escherichia coli MutY (MYH) glycosylase]. Additional repair mechanisms for 8-OHdG are MMR that prevent 8-OHdG from pairing to A during genome replication and the human homolog of E. coli MuT (MTH) enzyme that repairs 8-OHdG nucleotide prior to inserting to DNA [23]. Other DNA lesion occurring in mesothelioma and repaired from BER elements are single strand breaks [20,24]. As noted before XRCC1 is a member of the core proteins of BER system contributing also to SSB repair. In asbestosexposed subjects, increased risk of MM was noted for the single nucleotide polymorphism (SNP) XRCC1-399Q that substitutes Arg to Gln in position 399 [odds ratio (OR) = 2.15; confidence intervals (CIs) = 1.08–4.28] [25]. This polymorphism lies in the region of the XRCC1 molecule, responsible for interaction with the protein PCNA and repair of SSB [26], but substitution of Arg to Gln could also affect the connection of XRCC1 with other members of the BER family including glycosylases [27]. Although in an in vitro study this SNP did not show defects for DNA repair [28], the 399Q allele has been associated with increased DNA damage in vivo and multiple human cancers [29]. In accordance with the aforementioned study, the SNP XRCC1-399Q was also shown to correlate with MM in a recent study for asbestos exposed subjects [30]. In contrast, no correlation was found between XRCC1-399Q and MM when this was assessed independent of asbestos exposure [31]. Other proteins of the BER system have been also implicated in MM pathogenesis. Increased expression and activity of APE was noted in rat pleural mesothelial cells secondary to crocidolite asbestos exposure in vitro [32]. Two studies have searched the correlation of the D148E (rs3136820) SNP of APE to MM but showed no significant results [30,31]. However, a meta-analysis of the two studies revealed a significant correlation of APE D148E with MM (OR 1.72, 95% CIs 1.02–2.91) [30]. It is worth noticing that this SNP has not been found to alter the endonuclease activity of APE [33], although correlated with other human cancers, as well [34]. The implication of Ogg1 in MM development has also been studied. The polymorphism S326C although found in vitro to suppress the action of Ogg1 [35], was not associated in clinical studies with a significant increase in MM [25,30,31]. On the other hand, deletions of 3p chromosome have been reported in MM, the region that Ogg1 gene is located [36,37]. Several other studies have implicated BER family proteins in MM pathophysiology. PARP was upregulated and activated in human mesothelial cells following asbestos exposure [38,39]. Indeed, PARP inhibition resulted in a potentiation in SSB formation following direct asbestos exposure of human mesothelial cells [40]. Interestingly, beside its role in DNA repair [41], PARP has been implicated in induction of apoptosis and cell death following asbestos exposure [19,38,39]. Gene expression analysis has also revealed an overexpression of three genes involved in BER encoding for
D. Toumpanakis, S.E. Theocharis / Cancer Letters 312 (2011) 143–149 Table 1 Altered gene expression of proteins of DNA repair systems reported in malignant mesothelioma. DNA repair system
Genes upregulated
Genes downregulated
Ref.
BER
PCNA, FEN1, Ung2, PARPa p44 MSH6 RAD50, RAD54L, RAD21, BRCA2, FANCA, FANCD2 XRCC4, Ku80a Rad18
Ung2
[38,39,42,44]
– – –
[42] [42] [42]
– –
[42,71] [42]
NER MMR HR
NHEJ TLS a
Data from in vitro studies.
Table 2 Polymorphisms of genes encoding proteins of DNA repair systems associated with risk for malignant mesothelioma. DNA repair system
Gene
Polymorphism
Correlation with MM
Ref.
BER
XRCC1
rs25487, Arg399Gln
Increased risk between asbestos exposed subjects for the Gln allele Increased risk for MM for Glu homozygotes Increased risk for MM for CT heterozygotes Increased DNA damage for the A allele between mineral fiber exposed workers Increased methylation of MGMT promoter with T allele
[25,30]
145
group C (XPC) protein recognizes DNA helix distorting lesions throughout the genome. Following, both the complex transcription factor IIH (TFIIH) with helicase activity and the endonuclease XPG are recruited to the lesion. In TC-NER, the DNA repair is initiated when a DNA lesion causes RNA polymerase II to stall during transcription. This leads to recruitment of various proteins, including the transcription factor TFIIH and XPG endonuclease [46,47]. The remaining repair process is common for both subpathways [7,14,45,48]. Initially, the proteins XPA and replication factor A (RPA) are recruited, responsible for confirming the presence of DNA damage and stabilizing the open bubble structures of the DNA helices (accomplished by the action of the helicases XPB and XPD, units of the factor TFIIH), respectively. Following, the dimer Excision repair cross-complementing group 1 (ERCC1)–XPG with endonuclease activity is recruited. An oligonucleotide around the DNA lesion (24–32 bases) is cleaved by the action of XPG and ERCC1 and the classical DNA replication machinery completes DNA repair. Interestingly, XPA contributes to ERCC1 recruitment and activation of XPG endonuclease [46]. 2.4. Malignant mesothelioma and nucleotide excision repair
BER
APE
rs313682, Asp148Glu
NER
ERCC1
NER
XPA
rs11615, Asn118Asn (C/T) rs1800975, A23G (noncoding region)
Direct repair
MGMT
rs16906252, C-56T (noncoding region)
[30]
[30]
[52]
[78]
proteins PCNA, FEN1 and the uracil-DNA glycosylase 2 (Ung2) [42] (an uracil glycosylase repairing misincorporation of uracil or deamination of cytosine [43]). In contrast, Singhal et al. reported downregulation of Ung2 gene in MM [44]. (A summary of DNA repair gene expression in MM is presented in Table 1.). Recent studies have also assessed possible associations of MM risk with SNPs for the proteins of the BER family, PCNA, PARP, ligase1, hMYH and polb, without producing significant correlations [30,31]. (For a summary of SNPs associated with MM see Table 2.) 2.3. Nucleotide excision repair NER is a crucial repair system against helix distorting DNA lesions, including those produced by anti-cancer agents [7,10]. NER is divided into two subpathways depending on the mechanism by which DNA damage is recognized; the global genome nucleotide excision repair (GG-NER) and transcription coupled repair (TC-NER) [45]. In GG-NER, a protein complex containing the Xeroderma Pigmentosum
Various studies have searched the implication of proteins of the NER family in MM development. A significant correlation of the SNP N118N (C > T) of ERCC1 with MM has been reported (heterozygotes OR = 1.59, CIs = 1.01– 2.50) [30]. Since ERCC1 contributes also to repair of interstrand links [49], this polymorphism could play a role in resistance to cisplatin therapy. Although, in vitro this SNP did not alter ERCC1 expression or platinum sensitivity [50], it was associated with response to cisplatin treatment in patients with non-small cell lung cancer [51]. In workers exposed to mineral fibers, including asbestos, increased DNA damage was noticed associated with the presence of adenosine (A) nucleotide in the SNP A23G of XPA gene [52]. This polymorphism lies on the 50 untranslated region of XPA gene but its effect on XPA expression and function is not known. The G allele has been correlated with increased DNA repair capacity [53] and reduced risk for lung cancer [53,54]. Gene expression study in patients with MM also revealed an up-regulation of the p44 gene expression that encodes a subunit of TFIIH core [42]. SNPs in the genes of XPD and XPG have been also studied for possible correlations with MM risk without raising however significant results [25,30,31]. 2.5. Mismatch repair system MMR system corrects mispaired nucleotides formed by replication errors, as well as insertion/deletion loops that arise from strand slippage during replication of repetitive sequences [7]. Proteins of the MMR system in human are referred to as homologs of the E. coli MMR system and include proteins MSH2, MSH3, MSH6 (homologs of MutS), proteins MLH1, MLH3, PMS1, PMS2 (homologs of MutL), while homologs for MutH have not been yet identified [55]. The heterodimer MSH2/6 (MutSa) recognizes mismatches and small DNA loops, while the dimer MSH2/3
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(MSHb) bind to larger insertion/deletion loops [7,56]. Following DNA strand discrimination, MutL homologs form heterodimers that interact with MutS and various downstream proteins [55]. Excision of the strand containing the mismatch and DNA refilling is achieved by various protein components including pold/e, RPA, PCNA and DNA ligase1 [7,55]. 2.6. Malignant mesothelioma and mismatch repair To our knowledge, there is lack of evidence in literature for the implication of MMR in MM. Genome analysis has revealed an upregulation of MSH6 gene expression in MM [42]. Moreover, no significant correlation were found between various SNPs of MLH1, MSH2, MSH3 and MSH6 genes and the risk for MM development [31]. 2.7. Recombination repair system (homologous recombination – end joining) Recombination repair corrects DNA double-strand breaks (DSBs) and interstrand cross links [7]. The sources of DSBs in mammalian cells are among others environmental factors such as ionizing radiation, chemicals (including anti-tumor agents), unrepaired single strand breaks, stalled or collapsed DNA replication forks [45,57]. DSBs are repaired by two systems; HR, where repair is based on connection with the sister chromatid and is error free and NHEJ, which consists of direct break ligation and is error prone [7]. An initial event in DSBs is the recruitment and activation of the ataxia telengiectasia mutated (ATM) and ataxia telengiectasia related (ATR) proteins with multiple downstream substrates participating in cell cycle arrest (through activation of p53) and DNA repair process [including the Mre11-Nbs1-RAD50 (MNR) complex] [58,59]. When homologous recombination is preferred for DNA repair a multi-step process is performed including the exposure of the 30 -OH ends by MNR complex, formation of nucleoprotein filaments (involves the proteins RAD51, XRCC2, XRCC3), strand connection with a homologous sequence, DNA synthesis and resolve of the DNA connections (called Holliday junctions). Many other protein contribute to HR, including RAD52, RAD54, RPA and Breast Cancer 1 and 2 (BRCA1/2) [7,59,60]. In NHEJ, DSBs are recognized by the KU70/80 dimer initiating the repair cascade. Joining of DSBs ends is then performed by the action of the Artemis/DNAdependent protein kinase (DNA-PKcs) complex (with endonuclease activity) and XRCC4-ligase4 complex. Poll and k can fill DNA gaps arising during repair process [61,62]. 2.8. Malignant mesothelioma and homologous recombination As mentioned before, homologous recombination repairs DSBs and interstrand crosslinks. This is of great importance, since DSBs induce major chromosomal lesions, including deletions and translocations and can result in cell death [59]. Asbestos exposure has been found to induce DSBs in mesothelial cells [19,20] and chromosomal deletions are very common in malignant mesothelioma [36,37].
An analysis of gene expression in MM, revealed an upregulation of various genes encoding HR protein members, including proteins RAD50, RAD54L, RAD21 and BRCA2 [42]. On the other hand, loss of heterozygosity has been noted in MM for the regions 15q11.1-15 and 13q12-14 where genes for the RAD51 and BRCA2 locate [63]. Moreover, no SNP of genes encoding for HR protein members (RAD51, RAD52, RAD54, XRCC2, XRCC3, BRCA1 and BRCA2) had a significant correlation for MM development [31]. Although impaired DNA repair could promote mutagenesis, an intact HR repair system may increase resistance to radiotherapy and chemotherapy [10]. Indeed, increased expression of BRCA1 and BRCA2 was found in MM cell lines and treatment with extracellular regulated kinase inhibitors increased sensitivity to doxorubicin, through many mechanisms including defect DNA repair by lowering BRCA2 levels [64]. Interestingly, members of the Fanconi Anemia (FA) protein family were also upregulated in MM, including Fanconi Anemia complementation group A and D2 (FANCA and FANCD2) [42]. When activated by DNA damage, the FA pathway leads to mono-ubiquitylation of FANCD2 that interacts with others proteins, including ATM, BRCA1 and BRCA2 promoting DNA repair by homologous recombination [65,66]. DNA damage results in activation of p53 and cell cycle arrest to allow DNA repair or induces cell apoptosis. Although mutations in p53 gene are common in human cancers, no point mutations has been found in MM [67]. Moreover, expression of p53 is usually normal in mesothelioma [42] and various SNPs of the p53 gene were not associated with the risk for MM [31]. However, infection with virus SV40, a potential co-factor for MM [2], results in p53 inactivation through interaction of p53 with the protein Tag encoded by the virus DNA [68]. Inactivation of p53 in MM could also result from down-regulation of its activator open reading frame protein (p14/ARF), since the gene encoding p14/ARF is located in the 19p21-22 region that is frequently deleted in MM [36,69]. Indeed, transgenic mice with deletions of p14/ARF gene showed increased incidence and shorter latency time for MM development following asbestos exposure [70]. 2.9. Malignant mesothelioma and nonhomologous end joining The implication of various members of the NHEJ repair family in MM has been reported. Overexpression of the gene encoding for the protein Ku80 has been found in mesothelioma cell lines [71]. In another study, SNPs of the gene were not associated with the risk for MM [31]. Interestingly, XRCC4, a key gene of NHEJ, is also upregulated in MM [42]. Since NHEJ repairs DSBs that are also formed during anti-cancer therapy (e.g. by ionizing radiation and topoisomerases inhibitors) [10], the implication of NHEJ in MM could provide novel therapeutical targets. On the other hand, a point mutation of the gene encoding the protein Ku70 has been detected in a patient with pleural MM that results in V296M amino acid substitution in the region that contacts Ku80 [72]. Defective action of the Ku70/Ku80 dimer could impair DNA repair and promote mutagenesis.
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2.10. Additional mechanisms of DNA repair Further DNA repair enzymes are single proteins that revert directly the DNA lesion, including O6-methylguanine methyltransferase (O6-MGMT) that removes methyl groups from O6 position of guanine, a highly mutagenic DNA lesion that results in G/C to A/T conversion [7,73]. In addition to DNA repair systems, the cells employ mechanisms to bypass DNA lesions during replication, a process called ‘‘translesion synthesis’’ (TLS). This consists of replacing regular DNA polymerases when a damaged site is encountered, by translesion polymerases (polf-j) that replicate DNA with lesser base-pairing requirements (with the action of additional factors) [11,74]. 2.11. Malignant mesothelioma and direct repair of DNA lesions MGMT gene expression is under epigenetic control and suppressed by methylation of its promoter in CpG islands [75]. Methylation of the promoter of MGMT gene is common in human cancer [76]. Moreover, since alkylation of O6 sites is among the mechanisms of the alkylating chemotherapeutic drugs, depressed MGMT activity could enhance their therapeutic action [73]. DNA methylation is found in various loci in MM [77]. Kristensen et al. studied biopsies from 95 patients with pleural MM and detected methylation of the promoter of MGMT gene in 13 of them [78]. Interestingly, methylation status was correlated with the T allele of the rs16906252 polymorphism, in accordance with studies on colorectal cancer [79]. However, gene silencing was a rare event, limiting MGMT value in MM pathogenesis [78]. 2.12. Malignant mesothelioma and translesion synthesis An important step of the bypass replication during TLS is the mono-ubiquitylation of PCNA mediated by Rad6/ Rad18 [80]. Rad18 has been found to be upregulated in MM [42]. Since translesion synthesis is implicated in repair of interstrand crosslinks, the upregulation of Rad18 could possible contribute to resistance to anti-cancer agents, including cisplatin and mitomycin C [81]. It is worth mentioning that PCNA is a protein with multiple functions in DNA replication and repair, including BER, NER, MMR and translesion synthesis [82]. Although, immunohistological detection of PCNA is not included in current European guidelines for management of pleural MM [3], PCNA has been reported to discriminate between MM and mesothelial hyperplasia and to possess prognostic value [83,84]. 3. Conclusion In conclusion, as presented in this review, several studies have provided accumulating data for the implication of DNA repair mechanisms in MM pathogenesis. Defective repair mechanisms caused by either lowered gene expression or single nucleotide polymorphisms (Table 2) that affect enzyme function, can augment mutagenesis and act synergistically to asbestos exposure. The latter raises also the issue of a more individualized
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approach to disease progression. On the other hand, increased expression (Table 1) and activity of DNA repair enzymes may protect mesothelial cells from asbestosinduced DNA damage but augments resistance to chemoand radiotherapy of MM tumor cells. Thus, blocking the activated DNA repair enzymes or extending DNA repair deficiency in tumors already presenting DNA repair defects could provide novel targets for the treatment of MM as single therapy or in combination with standard anti-cancer therapy.
References [1] B.W. Robinson, R.A. Lake, Advances in malignant mesothelioma, New Engl. J. Med. 353 (2005) 1591–1603. [2] B.W. Robinson, A.W. Musk, R.A. Lake, Malignant mesothelioma, Lancet 366 (2005) 397–408. [3] A. Scherpereel, P. Astoul, P. Baas, T. Berghmans, H. Clayson, P. de Vuyst, H. Dienemann, F. Galateau-Salle, C. Hennequin, G. Hillerdal, C. Le Pechoux, L. Mutti, J.C. Pairon, R. Stahel, P. van Houtte, J. van Meerbeeck, D. Waller, W. Weder, Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma, Eur. Respir. J. 35 (2010) 479–495. [4] N.H. Heintz, Y.M. Janssen-Heininger, B.T. Mossman, Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways, Am. J. Respir. Cell Mol. Biol. 42 (2010) 133–139. [5] N. Choe, S. Tanaka, E. Kagan, Asbestos fibers and interleukin-1 upregulate the formation of reactive nitrogen species in rat pleural mesothelial cells, Am. J. Respir. Cell Mol. Biol. 19 (1998) 226–236. [6] S.P. Hussain, C.C. Harris, Inflammation and cancer: an ancient link with novel potentials, Int. J. Cancer 121 (2007) 2373–2380. [7] J.H. Hoeijmakers, Genome maintenance mechanisms for preventing cancer, Nature 411 (2001) 366–374. [8] L.A. Loeb, K.R. Loeb, J.P. Anderson, Multiple mutations and cancer, Proc. Natl Acad. Sci. USA 100 (2003) 776–781. [9] M.R. Stratton, P.J. Campbell, P.A. Futreal, The cancer genome, Nature 458 (2009) 719–724. [10] T. Helleday, E. Petermann, C. Lundin, B. Hodgson, R.A. Sharma, DNA repair pathways as targets for cancer therapy, Nat. Rev. Cancer 8 (2008) 193–204. [11] S.P. Jackson, J. Bartek, The DNA-damage response in human biology and disease, Nature 461 (2009) 1071–1078. [12] H. Farmer, N. McCabe, C.J. Lord, A.N. Tutt, D.A. Johnson, T.B. Richardson, M. Santarosa, K.J. Dillon, I. Hickson, C. Knights, N.M. Martin, S.P. Jackson, G.C. Smith, A. Ashworth, Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, Nature 434 (2005) 917–921. [13] S.A. Martin, C.J. Lord, A. Ashworth, DNA repair deficiency as a therapeutic target in cancer, Curr. Opin. Genet. Dev. 18 (2008) 80– 86. [14] T. Lindahl, R.D. Wood, Quality control by DNA repair, Science 286 (1999) 1897–1905. [15] E. Gatzidou, C. Michailidi, S. Tseleni-Balafouta, S. Theocharis, An epitome of DNA repair related genes and mechanisms in thyroid carcinoma, Cancer Lett. 290 (2010) 139–147. [16] T. Lindahl, Suppression of spontaneous mutagenesis in human cells by DNA base excision-repair, Mutat. Res. 462 (2000) 129–135. [17] H.E. Krokan, H. Nilsen, F. Skorpen, M. Otterlei, G. Slupphaug, Base excision repair of DNA in mammalian cells, FEBS Lett. 476 (2000) 73–77. [18] M.L. Hegde, T.K. Hazra, S. Mitra, Early steps in the DNA base excision/ single-strand interruption repair pathway in mammalian cells, Cell Res. 18 (2008) 27–47. [19] D. Upadhyay, D.W. Kamp, Asbestos-induced pulmonary toxicity: role of DNA damage and apoptosis, Exp. Biol. Med. (Maywood.) 228 (2003) 650–659. [20] M.C. Jaurand, Mechanisms of fiber-induced genotoxicity, Environ. Health Perspect. 105 (Suppl. 5) (1997) 1073–1084. [21] Q. Chen, J. Marsh, B. Ames, B. Mossman, Detection of 8-oxo-20 deoxyguanosine, a marker of oxidative DNA damage, in culture medium from human mesothelial cells exposed to crocidolite asbestos, Carcinogenesis 17 (1996) 2525–2527.
148
D. Toumpanakis, S.E. Theocharis / Cancer Letters 312 (2011) 143–149
[22] K. Unfried, C. Schurkes, J. Abel, Distinct spectrum of mutations induced by crocidolite asbestos: clue for 8-hydroxydeoxyguanosinedependent mutagenesis in vivo, Cancer Res. 62 (2002) 99–104. [23] P. Fortini, B. Pascucci, E. Parlanti, M. D’Errico, V. Simonelli, E. Dogliotti, 8-Oxoguanine DNA damage: at the crossroad of alternative repair pathways, Mutat. Res. 531 (2003) 127–139. [24] T. Ollikainen, K. Linnainmaa, V.L. Kinnula, DNA single strand breaks induced by asbestos fibers in human pleural mesothelial cells in vitro, Environ. Mol. Mutagen. 33 (1999) 153–160. [25] I. Dianzani, L. Gibello, A. Biava, M. Giordano, M. Bertolotti, M. Betti, D. Ferrante, S. Guarrera, G.P. Betta, D. Mirabelli, G. Matullo, C. Magnani, Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study, Mutat. Res. 599 (2006) 124–134. [26] K.W. Caldecott, XRCC1 and DNA strand break repair, DNA Repair (Amst) 2 (2003) 955–969. [27] R. Monaco, R. Rosal, M.A. Dolan, M.R. Pincus, P.W. Brandt-Rauf, Conformational effects of a common codon 399 polymorphism on the BRCT1 domain of the XRCC1 protein, Protein J. 26 (2007) 541– 546. [28] R.M. Taylor, A. Thistlethwaite, K.W. Caldecott, Central role for the XRCC1 BRCT I domain in mammalian DNA single-strand break repair, Mol. Cell. Biol. 22 (2002) 2556–2563. [29] W. Ladiges, J. Wiley, A. MacAuley, Polymorphisms in the DNA repair gene XRCC1 and age-related disease, Mech. Ageing Dev. 124 (2003) 27–32. [30] M. Betti, D. Ferrante, M. Padoan, S. Guarrera, M. Giordano, A. Aspesi, D. Mirabelli, C. Casadio, F. Ardissone, E. Ruffini, P.G. Betta, R. Libener, R. Guaschino, G. Matullo, E. Piccolini, C. Magnani, I. Dianzani, XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a casecontrol study, Mutat. Res. 708 (2011) 11–20. [31] F. Gemignani, M. Neri, F. Bottari, R. Barale, P.A. Canessa, F. Canzian, M. Ceppi, I. Spitaleri, M. Cipollini, G.P. Ivaldi, M. Mencoboni, P. Scaruffi, G.P. Tonini, D. Ugolini, L. Mutti, S. Bonassi, S. Landi, Risk of malignant pleural mesothelioma and polymorphisms in genes involved in the genome stability and xenobiotics metabolism, Mutat. Res. 671 (2009) 76–83. [32] H. Fung, Y.W. Kow, B. Van Houten, D.J. Taatjes, Z. Hatahet, Y.M. Janssen, P. Vacek, S.P. Faux, B.T. Mossman, Asbestos increases mammalian AP-endonuclease gene expression, protein levels, and enzyme activity in mesothelial cells, Cancer Res. 58 (1998) 189–194. [33] S. Daviet, S. Couve-Privat, L. Gros, K. Shinozuka, H. Ide, M. Saparbaev, A.A. Ishchenko, Major oxidative products of cytosine are substrates for the nucleotide incision repair pathway, DNA Repair (Amst) 6 (2007) 8–18. [34] J.J. Hu, T.R. Smith, M.S. Miller, K. Lohman, L.D. Case, Genetic regulation of ionizing radiation sensitivity and breast cancer risk, Environ. Mol. Mutagen. 39 (2002) 208–215. [35] A. Yamane, T. Kohno, K. Ito, N. Sunaga, K. Aoki, K. Yoshimura, H. Murakami, Y. Nojima, J. Yokota, Differential ability of polymorphic OGG1 proteins to suppress mutagenesis induced by 8hydroxyguanine in human cell in vivo, Carcinogenesis 25 (2004) 1689–1694. [36] T. Taguchi, S.C. Jhanwar, J.M. Siegfried, S.M. Keller, J.R. Testa, Recurrent deletions of specific chromosomal sites in 1p, 3p, 6q, and 9p in human malignant mesothelioma, Cancer Res. 53 (1993) 4349–4355. [37] S. Neragi-Miandoab, D.J. Sugarbaker, Chromosomal deletion in patients with malignant pleural mesothelioma, Interact. Cardiovasc. Thorac. Surg. 9 (2009) 42–44. [38] H. Yang, Z. Rivera, S. Jube, M. Nasu, P. Bertino, C. Goparaju, G. Franzoso, M.T. Lotze, T. Krausz, H.I. Pass, M.E. Bianchi, M. Carbone, Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation, Proc. Natl. Acad. Sci. USA 107 (2010) 12611–12616. [39] V.C. Broaddus, L. Yang, L.M. Scavo, J.D. Ernst, A.M. Boylan, Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species, J. Clin. Invest. 98 (1996) 2050–2059. [40] T. Ollikainen, A. Puhakka, K. Kahlos, K. Linnainmaa, V.L. Kinnula, Modulation of cell and DNA damage by poly(ADP)ribose polymerase in lung cells exposed to H(2)O(2) or asbestos fibres, Mutat. Res. 470 (2000) 77–84. [41] H.Y. Dong, A. Buard, F. Levy, A. Renier, F. Laval, M.C. Jaurand, Synthesis of poly(ADP-ribose) in asbestos treated rat pleural mesothelial cells in culture, Mutat. Res. 331 (1995) 197–204. [42] O.D. Roe, E. Anderssen, H. Sandeck, T. Christensen, E. Larsson, S. Lundgren, Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets, Lung Cancer 67 (2010) 57–68.
[43] H.E. Krokan, R. Standal, G. Slupphaug, DNA glycosylases in the base excision repair of DNA, Biochem. J. 325 (Pt. 1) (1997) 1–16. [44] S. Singhal, R. Wiewrodt, L.D. Malden, K.M. Amin, K. Matzie, J. Friedberg, J.C. Kucharczuk, L.A. Litzky, S.W. Johnson, L.R. Kaiser, S.M. Albelda, Gene expression profiling of malignant mesothelioma, Clin. Cancer Res. 9 (2003) 3080–3097. [45] C.L. Peterson, J. Cote, Cellular machineries for chromosomal DNA repair, Genes Dev. 18 (2004) 602–616. [46] M. Volker, M.J. Mone, P. Karmakar, A. van Hoffen, W. Schul, W. Vermeulen, J.H. Hoeijmakers, R. van Driel, A.A. van Zeeland, L.H. Mullenders, Sequential assembly of the nucleotide excision repair factors in vivo, Mol. Cell 8 (2001) 213–224. [47] R. Dip, U. Camenisch, H. Naegeli, Mechanisms of DNA damage recognition and strand discrimination in human nucleotide excision repair, DNA Repair (Amst) 3 (2004) 1409–1423. [48] J.R. Mitchell, J.H. Hoeijmakers, L.J. Niedernhofer, Divide and conquer: nucleotide excision repair battles cancer and ageing, Curr. Opin. Cell Biol. 15 (2003) 232–240. [49] D.T. Bergstralh, J. Sekelsky, Interstrand crosslink repair: can XPFERCC1 be let off the hook?, Trends Genet 24 (2008) 70–76. [50] R. Gao, K. Reece, T. Sissung, E. Reed, D.K. Price, W.D. Figg, The ERCC1 N118N polymorphism does not change cellular ERCC1 protein expression or platinum sensitivity, Mutat. Res. 708 (2011) 21–27. [51] A. Kalikaki, M. Kanaki, H. Vassalou, J. Souglakos, A. Voutsina, V. Georgoulias, D. Mavroudis, DNA repair gene polymorphisms predict favorable clinical outcome in advanced non-small-cell lung cancer, Clin. Lung Cancer 10 (2009) 118–123. [52] M. Dusinska, Z. Dzupinkova, L. Wsolova, V. Harrington, A.R. Collins, Possible involvement of XPA in repair of oxidative DNA damage deduced from analysis of damage, repair and genotype in a human population stud, Mutagenesis 21 (2006) 205–211. [53] X. Wu, H. Zhao, Q. Wei, C.I. Amos, K. Zhang, Z. Guo, Y. Qiao, W.K. Hong, M.R. Spitz, XPA polymorphism associated with reduced lung cancer risk and a modulating effect on nucleotide excision repair capacity, Carcinogenesis 24 (2003) 505–509. [54] J.Y. Park, S.H. Park, J.E. Choi, S.Y. Lee, H.S. Jeon, S.I. Cha, C.H. Kim, J.H. Park, S. Kam, R.W. Park, I.S. Kim, T.H. Jung, Polymorphisms of the DNA repair gene xeroderma pigmentosum group A and risk of primary lung cancer, Cancer Epidemiol. Biomarkers Prev. 11 (2002) 993–997. [55] G.M. Li, Mechanisms and functions of DNA mismatch repair, Cell Res. 18 (2008) 85–98. [56] B.D. Harfe, S. Jinks-Robertson, DNA mismatch repair and genetic instability, Annu. Rev. Genet. 34 (2000) 359–399. [57] K.K. Khanna, S.P. Jackson, DNA double-strand breaks: signaling, repair and the cancer connection, Nat. Genet. 27 (2001) 247–254. [58] L.H. Thompson, D. Schild, Recombinational DNA repair and human disease, Mutat. Res. 509 (2002) 49–78. [59] M. Shrivastav, L.P. De Haro, J.A. Nickoloff, Regulation of DNA doublestrand break repair pathway choice, Cell Res. 18 (2008) 134–147. [60] J. San Filippo, P. Sung, H. Klein, Mechanism of eukaryotic homologous recombination, Annu. Rev. Biochem. 77 (2008) 229–257. [61] M.R. Lieber, The mechanism of human nonhomologous DNA end joining, J. Biol. Chem. 283 (2008) 1–5. [62] M.R. Lieber, The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway, Annu. Rev. Biochem. 79 (2010) 181–211. [63] B.R. Balsara, D.W. Bell, G. Sonoda, A. De Rienzo, M.S. Du, S.C. Jhanwar, J.R. Testa, Comparative genomic hybridization and loss of heterozygosity analyses identify a common region of deletion at 15q11.1-15 in human malignant mesothelioma, Cancer Res. 59 (1999) 450–454. [64] A. Shukla, J.M. Hillegass, M.B. MacPherson, S.L. Beuschel, P.M. Vacek, H.I. Pass, M. Carbone, J.R. Testa, B.T. Mossman, Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin, Mol. Cancer 9 (2010) 314. [65] K.J. Patel, H. Joenje, Fanconi anemia and DNA replication repair, DNA Repair (Amst) 6 (2007) 885–890. [66] A.D. D’Andrea, M. Grompe, The Fanconi anaemia/BRCA pathway, Nat. Rev. Cancer 3 (2003) 23–34. [67] O. Mor, P. Yaron, M. Huszar, A. Yellin, O. Jakobovitz, F. Brok-Simoni, G. Rechavi, N. Reichert, Absence of p53 mutations in malignant mesotheliomas, Am. J. Respir. Cell Mol. Biol. 16 (1997) 9–13. [68] J.R. Testa, A. Giordano, SV40 and cell cycle perturbations in malignant mesothelioma, Semin. Cancer Biol. 11 (2001) 31–38. [69] J.Q. Cheng, S.C. Jhanwar, W.M. Klein, D.W. Bell, W.C. Lee, D.A. Altomare, T. Nobori, O.I. Olopade, A.J. Buckler, J.R. Testa, P16 alterations and deletion mapping of 9p21–p22 in malignant mesothelioma, Cancer Res. 54 (1994) 5547–5551.
D. Toumpanakis, S.E. Theocharis / Cancer Letters 312 (2011) 143–149 [70] D.A. Altomare, C.W. Menges, J. Xu, J. Pei, L. Zhang, A. Tadevosyan, E. Neumann-Domer, Z. Liu, M. Carbone, I. Chudoba, A.J. KleinSzanto, J.R. Testa, Losses of both products of the cdkn2a/arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis, PLoS ONE 6 (2011) e18828. [71] E. Kettunen, A.M. Nissen, T. Ollikainen, M. Taavitsainen, J. Tapper, K. Mattson, K. Linnainmaa, S. Knuutila, W. El Rifai, Gene expression profiling of malignant mesothelioma cell lines: cDNA array study, Int. J. Cancer 91 (2001) 492–496. [72] D.J. Sugarbaker, W.G. Richards, G.J. Gordon, L. Dong, A. De Rienzo, G. Maulik, J.N. Glickman, L.R. Chirieac, M.L. Hartman, B.E. Taillon, L. Du, P. Bouffard, S.F. Kingsmore, N.A. Miller, A.D. Farmer, R.V. Jensen, S.R. Gullans, R. Bueno, Transcriptome sequencing of malignant pleural mesothelioma tumors, Proc. Natl. Acad. Sci. USA 105 (2008) 3521– 3526. [73] M. Esteller, J.G. Herman, Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer, Oncogene 23 (2004) 1–8. [74] A.R. Lehmann, Replication of damaged DNA by translesion synthesis in human cells, FEBS Lett. 579 (2005) 873–876. [75] G.S. Watts, R.O. Pieper, J.F. Costello, Y.M. Peng, W.S. Dalton, B.W. Futscher, Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene, Mol. Cell. Biol. 17 (1997) 5612–5619. [76] M. Esteller, S.R. Hamilton, P.C. Burger, S.B. Baylin, J.G. Herman, Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia, Cancer Res. 59 (1999) 793– 797. [77] J.A. Tsou, J.S. Galler, A. Wali, W. Ye, K.D. Siegmund, S. Groshen, P.W. Laird, S. Turla, M.N. Koss, H.I. Pass, I.A. Laird-Offringa, DNA
[78]
[79]
[80]
[81]
[82] [83]
[84]
149
methylation profile of 28 potential marker loci in malignant mesothelioma, Lung Cancer 58 (2007) 220–230. L.S. Kristensen, H.M. Nielsen, H. Hager, L.L. Hansen, Methylation of MGMT in malignant pleural mesothelioma occurs in a subset of patients and is associated with the T allele of the rs16906252 MGMT promoter SNP, Lung Cancer 71 (2011) 130–136. S. Ogino, A. Hazra, G.J. Tranah, G.J. Kirkner, T. Kawasaki, K. Nosho, M. Ohnishi, Y. Suemoto, J.A. Meyerhardt, D.J. Hunter, C.S. Fuchs, MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer, Carcinogenesis 28 (2007) 1985–1990. M. Shaheen, I. Shanmugam, R. Hromas, The role of PCNA posttranslational modifications in translesion synthesis, J. Nucleic Acids 2010 (2010). K. Nojima, H. Hochegger, A. Saberi, T. Fukushima, K. Kikuchi, M. Yoshimura, B.J. Orelli, D.K. Bishop, S. Hirano, M. Ohzeki, M. Ishiai, K. Yamamoto, M. Takata, H. Arakawa, J.M. Buerstedde, M. Yamazoe, T. Kawamoto, K. Araki, J.A. Takahashi, N. Hashimoto, S. Takeda, E. Sonoda, Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells, Cancer Res. 65 (2005) 11704–11711. G.L. Moldovan, B. Pfander, S. Jentsch, PCNA, the maestro of the replication fork, Cell 129 (2007) 665–679. V. Esposito, A. Baldi, A. De Luca, G. Paciocco, A. Groger, G. Sgaramella, P.P. Claudio, G.G. Giordano, F. Baldi, M. Caputi, H. Kaiser, A. Giordano, Role of PCNA in differentiating between malignant mesothelioma and mesothelial hyperplasia: prognostic considerations, Anticancer Res. 17 (1997) 601–604. M. Ramael, W. Jacobs, J. Weyler, J. van Meerbeeck, P. Bialasiewicz, B.J. Van den, C. Buysse, P. Vermeire, E. Van Marck, Proliferation in malignant mesothelioma as determined by mitosis counts and immunoreactivity for proliferating cell nuclear antigen (PCNA), J. Pathol. 172 (1994) 247–253.