Oxidatively damaged DNA and its repair in colon carcinogenesis

Mutation Research 736 (2012) 82–92

Contents lists available at SciVerse ScienceDirect

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis journal homepage: www.elsevier.com/locate/molmut Community address: www.elsevier.com/locate/mutres

Review

Oxidatively damaged DNA and its repair in colon carcinogenesis ˙ Barbara Tudek a,b , Elzbieta Speina a,∗ a b

Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawi´ nskiego 5a, 02-106 Warsaw, Poland Institute of Genetics and Biotechnology, Faculty of Biology, Warsaw University, Pawi´ nskiego 5a, 02-106 Warsaw, Poland

a r t i c l e

i n f o

Article history: Received 9 January 2012 Received in revised form 2 April 2012 Accepted 16 April 2012 Available online 25 April 2012 Keywords: Colorectal cancer Oxidative stress Lipid peroxidation 8-Oxo-7,8-dihydroguanine Etheno DNA adducts DNA repair

a b s t r a c t Inflammation, high fat, high red meat and low fiber consumption have for long been known as the most important etiological factors of sporadic colorectal cancers (CRC). Colon cancer originates from neoplastic transformation in a single layer of epithelial cells occupying colonic crypts, in which migration and apoptosis program becomes disrupted. This results in the formation of polyps and metastatic cancers. Mutational program in sporadic cancers involves APC gene, in which mutations occur most abundantly in the early phase of the process. This is followed by mutations in RAS, TP53, and other genes. Progression of carcinogenic process in the colon is accompanied by augmentation of the oxidative stress, which manifests in the increased level of oxidatively damaged DNA both in the colon epithelium, and in blood leukocytes and urine, already at the earliest stages of disease development. Defence mechanisms are deregulated in CRC patients: (i) antioxidative vitamins level in blood plasma declines with the development of disease; (ii) mRNA level of base excision repair enzymes in blood leukocytes of CRC patients is significantly increased; however, excision rate is regulated separately, being increased for 8oxoGua, while decreased for lipid peroxidation derived ethenoadducts, ␧Ade and ␧Cyt; (iii) excision rate of ␧Ade and ␧Cyt in colon tumors is significantly increased in comparison to asymptomatic colon margin, and ethenoadducts level is decreased. This review highlights mechanisms underlying such deregulation, which is the driving force to colon carcinogenesis. © 2012 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

4.

5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histopathology of CRC and mutations in critical genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidative stress in the development of colon cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Consumption of red meat and alcohol and tobacco smoking. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Repair of oxidative DNA damage as a driving force to colon carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Repair of 8-oxo-7,8-dihydro-2 -deoxyguanosine in colon adenoma and carcinoma patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Repair of etheno DNA adducts in colon carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aberrant repair of oxidatively damaged DNA bases and mutations in critical genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83 83 84 84 84 85 85 86 87 88 89 90 90 90

Abbreviations: 8-oxodG, 8-oxo-7,8-dihydro-2 -deoxyguanosine; 8-oxoGua, 8-oxo-7,8-dihydroguanine; AD, adenoma; CRC, colorectal cancer; APC, adenomatous polyposis coli; FapyGua, 2,6-diamino-4-hydroxy-5-formamidopyrimidine; APE1, apurinic site endonuclease 1; ROS, reactive oxygen species; RNS, reactive nitrogen species; BER, base excision repair; ␧Ade, 1,N6 -ethenoadenine; ␧dA, 1,N6 -etheno-2 -deoxyadenosine; ␧Cyt, 3,N4 -ethenocytosine; ␧dC, 3,N4 -etheno-2 -deoxycytidine; 1N2 -␧dG, 1,N2 etheno-2 -deoxyguanosine; LPO, lipid peroxidation; MMR, mismatch repair. ∗ Corresponding author. Tel.: +48 22 592 3334; fax: +48 22 592 2190. E-mail address: [email protected] (E. Speina). 0027-5107/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.mrfmmm.2012.04.003

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92

1. Introduction Colorectal cancer (CRC) is one of the most frequent causes of death in Western countries. The cases are roughly equally distributed between the sexes. Two main factors are considered in pathogenesis of this cancer: (i) inflammation and high fat diet [1], which increases the number of lesions in DNA and induces mutations in critical genes; and (ii) genetic predispositions. Inflammation is associated with the release of large amounts of reactive oxygen and nitrogen species [2] leading to oxidation of nucleic acids, proteins and lipids, and induction of several promutagenic DNA lesions. The genetic predisposition to CRC may be connected to the deficiency in mismatch repair system (MMR), which causes mutator phenotype of intestine cells (manifesting itself as microsatellites instability – MSI) and development of hereditary non-polyposis colon carcinoma – HNPCC (or Lynch syndrome). They may also be associated with the deficiency of the APC (adenomatous polyposis coli) gene product, which functions are related to Wnt signaling pathways and migration of intestine epithelium. Lack of APC protein leads to familial adenomatous polyposis (FAP), a well described syndrome characterized by multiple adenomatous lesions which usually appear in the second and third decades of life. The probability of malignant transformation of one of the polyps is close to 100% [3]. A subset of patients present an attenuated form (AFAP) characterized by fewer lesions (<100), a later age of onset, and a predilection for the proximal colon. About 10–15% of AFAP cases reveal mutations in APC gene. More frequently, in 20–30% of cases [4,5], AFAP has been correlated with a biallelic mutation of the MutY human homologue gene (MYH). MutY is a DNA glycosylase, which is involved in elimination from DNA of adenine incorrectly paired with 8-oxo-7,8-dihydroguanine (8-oxoGua). Oxidative DNA damage has been linked to various pathological conditions, such as aging, carcinogenesis, neurodegenerative and cardiovascular disease (reviewed by [6–9]). This review focuses on the role of oxidatively induced DNA lesions in colon carcinogenesis. We discuss the mechanisms of tumor initiation (generation of DNA damage and mutations) and multiple molecular steps in the colon cancer progression with special focus on the deregulation of defense mechanisms, such as anti-oxidant response and DNA repair.

2. Histopathology of CRC and mutations in critical genes A single layer of epithelial cells lines the crypts of the colon and rectum. Throughout the digestive tract, these crypts substantially increase the surface occupied by the epithelium. Four to six stem cells at the base of each crypt give rise to three epithelial cell types, absorptive cells, mucus-secreting goblet cells and epithelial cells. The cells multiply in the lower third of the crypts and differentiate in the upper two-thirds. Normally, the birth rate of the colonic epithelial cells precisely equals the rate of cell loss from the crypts apex to the lumen of the colon. The birth/loss ratio increases under neoplastic transformation of cells originating from a single progenitor cell. Polyp, a mass of cells protruding from the bowel wall is often the first observed syndrome of the development of colon cancer. However, according to official medical classifications colonic polyps are not recognized as cancer. There are two main types of polyps, which can be distinguished histologically but not by their external appearance [10]. The non-dysplastic or hyperplastic type contains large number of cells that have a normal morphology. Cell epithelium is lined up in a single row along the basement membrane, and these polyps apparently have little tendency to become neoplastic. Adenomatous polyp type is dysplastic, has abnormal intercellular organization. Several layers of

83

epithelial cells are observed; the nuclei of the epithelial cells are larger than normal, and their position within the cells is often aberrant. Crypts crowd together in kaleidoscopic pattern. As adenomas grow in size, they become more dysplastic. They are also more likely to contain “villous” components, i.e., fingerlike projections of dysplastic crypts that can be distinguished from the smooth contour of the less advanced “tubular” adenomas. As adenomas progress, they are likely to become malignant, defined as the ability for invading surrounding tissue and travel to distant organs through direct spread or transport by blood and lymphatic vessels. Malignant tumors are not necessarily larger or more dysplastic than benign tumors; their sole determining feature is invasiveness. Polyps are the earliest clinical manifestation of colorectal neoplasia. However, the earliest pre-carcinogenic changes in the colon can be observed under microscope after methylene blue staining or examination of the colonic mucosa cross sections (Fig. 1). These changes are termed aberrant crypt foci (ACF). Like their larger counterparts, can be either dysplastic or non-dysplastic. In mice or rats ACF are found as soon as 2–3 weeks following administration of colon carcinogens [11], they grow with time giving rise to malignant tumors 6 months after animal intoxication with carcinogen [12]. Consecutive stages of colon carcinogenesis are accompanied by acquiring mutations in critical genes, which regulate cell proliferation, and/or apoptosis. A relatively limited number of oncogenes and tumor suppressor genes, most prominently the APC, KRAS, and TP53 genes are mutated in CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. On the basis of the frequency of mutations occurring in different genes at particular stages of adenoma to carcinoma progression, the sequence of genetic changes was proposed [13]. We will briefly summarize the genetic events in order to shed light how these changes may affect the extent of oxidative DNA damage, and modulate its repair rate. The earliest genetic change in colon carcinogenesis is mutation in the APC gene. About 70–80% of sporadic adenomas and carcinomas have somatic mutation that inactivate the APC gene, and its frequency is similar in the earliest lesions, like microscopic adenomas composed of few dysplastic glands, and in advanced adenomas and carcinomas, independently of the efficiency of the MMR system. APC protein functions in the Wnt signaling pathway, in which stimulates proteasomal degradation of ␤-catenin, an activator of TCF/LET (T cell factor/lymphoid enhancer family) transcription factors family. In consequence APC inhibits transcription of several genes, such as proto-oncogenes, e.g., c-MYC or cyclin D1, genes encoding membrane factors – matrix metalloproteinase 7 (MMP-7)/Matrilysin, membrane type 1 MMP, laminin-5 2 chain, CD44, growth factors, e.g., FGF20, FGF9, and Wnt pathway feedback inhibitors, such as AXIN2, Naked-1/-2, Dickkopf-1, WNT inhibitory factor 1. Transcriptional program induced by ␤-catenin resembles the transcriptional program in stem cells at the base of the colon crypts [14]. Thus, activation of ␤-catenin caused by APC mutation will stimulate proliferation of epithelial cells in colonic crypts. Next, mutations in genes functioning in EGFR signaling pathway, such as K-RAS, BREF or PTEN will further enhance cell proliferation and survival, and drive progression of early adenomas to intermediate lesions. K-RAS is mutated in almost 40% of intermediate and late adenomas and carcinomas. Inactivation of TGF-␤ response, e.g., DCC (deleted in colorectal cancer) or TGF-ˇ receptor mutations cause loss of growth inhibitory effect of TGF-␤ and suppress apoptosis. These genetic changes are frequently observed in late adenoma lesions. Loss of TP53 function is the late genetic change, which further stimulates proliferation and survival promoting the shift of adenoma to carcinoma. TP53 mutations are observed in about 50% of colorectal cancers, but much less frequently in adenomas. At least two of these genetic changes, loss of APC and TP53 functions may affect DNA repair in colonic crypts, and in consequence the

84

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92

Fig. 1. Aberrant crypt foci. (A) A view from the lumen site of intact mouse colon. The colon was cut open along the longitudinal median axis, formalin fixed and stained with methylene blue. The mucosal side was observed under the light microscope (magnification 100×); (B and C) cross sections of mouse epithelium stained with hematoxylin and eosin (magnification 1000×).

extent of DNA damage, and potential of gaining new mutations (see Section 5). 3. Oxidative stress in the development of colon cancer The majority of pathological factors favoring development of colon cancer involve induction of oxidative stress in the colon, which is defined as overproduction of oxygen species combined with insufficiency in protective mechanisms of anti-oxidative defence [15,16]. Oxidative stress is involved in the production of DNA damage and mutations associated with the initiation or progression of human cancers [17,18]. The main pathological factors for the development of CRC are inflammation, fat metabolism, consumption of meat and alcohol and tobacco smoking. All these stimulate the release of ROS and RNS as well as lipid peroxidation (LPO) [1,19]. These compounds play a dual role in cells. At low or moderate concentrations they are mediators of specific physiological processes, whereas high concentrations can be detrimental to all components of the cell. 3.1. Inflammation Epidemiological studies suggest that inflammatory processes are linked with CRC. This is true particularly in the association of inflammatory bowel disease and colorectal cancer [20]. During inflammation activated macrophages release large amounts of ROS and RNS [2], which oxidize nucleic acids, proteins and lipids. Oxidation of polyunsaturated fatty acids generates reactive aldehydes unsaturated in ␣, ␤-positions which, in contrast to ROS and RNS, are relatively stable and can diffuse throughout the cell [19]. Short chain reactive aldehydes are classified into the following families: 2-alkenals (e.g., acrolein, crotonaldehyde, 2-hexenal), 4-hydroxy2-alkenals (e.g., 4-hydroxy-2-hexenal – HHE, 4-hydroxy-2-nonenal – HNE) and ketoaldehydes (e.g., malondialdehyde – MDA, glyoxal, 4-oxo-2-nonenal – ONE) [21]. Multiplicity of LPO products is tremendously augmented by the existence of stereoisomers of several of these compounds. Reactive aldehydes either react directly with DNA and proteins [22], or undergo further oxidation to more reactive epoxy

derivatives, such as 2,3-epoxy-4-hydroxynonanal [23]. The affinity of epoxidized LPO products to nucleic acids is much higher than to proteins. Epoxidation of enals may occur in the presence of hydrogen peroxide, but is also catalysed by enzymes producing inflammatory mediators, prostaglandins and leukotrienes, such as cyclooxygenase-2 (COX-2) and lipooxygenases (LOX) [24]. It was observed that COX-2 is overexpressed in 80% of colorectal cancer tissues [25,26]. Increased levels of COX-2 were observed in epithelial cells, inflammatory cells, as well as in stromal cells, but not in adjacent normal tissues [27]. COX-2 overexpression in Min (multiple intestinal neoplasia) mice was sufficient to induce mammary tumors [28]. The mechanism of tumor induction by COX-2 overexpression is complex, and involves the activity of its enzymatic end-products, prostanoids. A number of theories have been proposed to explain the role of tumor-derived prostanoids in promotion of angiogenesis, induction of tumor cell proliferation, suppression of immune response, and protection against apoptosis [29–31]. Additionally, it was shown that arachidonic acid (AA) metabolism mediated by COX-2 and 5-LOX results in the formation of heptanone-etheno (H␧)-DNA adducts. The H␧-DNA adducts are highly mutagenic in mammalian cells suggesting that these pathways could be (at least in part) responsible for the somatic mutations observed in tumorigenesis [32]. That is why inhibition of COX-2 by non-steroid anti-inflammatory drugs or RNA interference appeared a successful approach in colon cancer prevention [33,34]. 3.2. Consumption of red meat and alcohol and tobacco smoking Epidemiological and animal model studies have suggested that high intake of heme, present in red meat, is associated with an increased risk of colon cancer. Recently elucidated mechanisms suggest that heme induces DNA damage and cell proliferation of colonic epithelial cells via hydrogen peroxide produced by heme oxygenase. In Caco-2 cells the presence of heme oxygenase inhibitor, zinc protoporphyrin, reduced DNA damage (measured by a comet assay) triggered by hemin as well as cell hyperproliferation [35]. The effect of heme may be modified by LPO products. The preincubation of colon adenocarcinoma, SW480, cells with

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92

hemoglobin (Hb) and its subsequent exposure to linoleic acid hydroperoxides (LAOOH) led to an increase in cell death, malondialdehyde formation, and DNA fragmentation and these effects were related to the peroxide group and the heme present in Hb. SW480 cells treated with Hb and LAOOH presented a higher level of the modified DNA bases 8-oxoGua and 1,N2 -etheno-2 deoxyguanosine (1,N2 -␧Gua) compared to the control. Incubations with Hb led to an increase in intracellular iron levels, which correlated with DNA oxidation. Thus, Hb from either red meat or bowel bleeding caused by inflammatory processes could act as an enhancer of fatty acid hydroperoxide genotoxicity, and in consequence contribute to the accumulation of DNA lesions in colon cells [36]. Another frequently suggested risk factor for CRC development is chronic alcohol consumption. One of the factors which may contribute to the development of alcohol-associated cancer is the action of acetaldehyde, the first and most toxic metabolite of alcohol metabolism [37]. Acetaldehyde is produced by the oxidation of ethanol by hepatic NAD-dependent alcohol dehydrogenase and during threonine catabolism. Acetaldehyde reacts with 2 deoxyguanosine in DNA to form 1,N2 -propanodG and 1,N2 -␧dG [38]. Both these DNA lesions were described to derive also from lipid peroxidation [39,36]. In hepatic cancer model, lean and obese Zucker rats higher levels of etheno DNA adducts were observed in the liver DNA of alcohol-fed than in control animals. This increase was correlated with the induction of cytochrome P-450 isoform 2E1 [40]. Thus, the formation of exocyclic DNA adducts, like propanodG, 1,N2 -␧dG, ␧dA and ␧dC may be the important mechanism associated with acetaldehyde related cancer risk. The results of epidemiological studies also link tobacco smoking with the risk for CRC development. However, the obtained data are controversial, and the molecular mechanism remains unclear. Although in the leukocytes of lung cancer patients tobacco smoking increased the level of one of the major oxidatively damaged DNA base, 8-oxoGua [41], in CRC patients no effect of tobacco smoking on 8-oxoGua level in the leukocytes and 8-oxoGua urinary excretion was observed [42]. 3.3. DNA damage Oxidatively damaged DNA has been blamed for the physiological changes associated with degenerative diseases and cancer [43,44]. DNA damage caused by free radicals is the most heterogeneous group of DNA lesions due to the wide variety of deleterious molecules produced in cells in the conditions of oxidative stress. A plethora of damaged DNA bases are formed upon ROS attack on genetic material, several of them reveal strong promutagenic properties [45]. One of the major and best studied is 8-oxoGua, a typical biomarker of oxidative stress, which may play a role in carcinogenesis [46]. The presence of 8-oxo-7,8-dihydro-2 -deoxyguanosine (8-oxodG) residues in DNA leads to GC→TA transversions [47]. 8-OxodG is formed in DNA either via direct oxidation of nucleic acids or can be incorporated from the nucleotide pool by DNA polymerases, the latter process being an important source of DNA oxidation and genome instability [48,49]. LPO products may contribute to DNA damage to nearly the same extent as directly oxidized bases. There are distinct groups of linear and cyclic LPO specific DNA lesions. Malondialdehyde reacts in DNA with guanine, adenine and cytosine to form cyclic pyrimido[1,2␣]purine-10(3H)-one-2 -deoxyribose (M1 dG) adduct and linear N6 -(3-oxopropenyl)-2 -deoxyadenosine (M1 dA) and N4-(3oxopropenyl)-2 -deoxycytosine (M1 dC) adducts, respectively [50]. M1 dG is the major MDA-DNA adduct and was detected in human and rodent tissues. In Escherichia coli cells, it induces transversions to T and transitions to A with a frequency comparable with that of 8-oxoGua [15].

85

Exocyclic propano DNA adducts are formed by the attachment of unsaturated reactive aldehyde to ring and extra-ring nitrogen atoms in DNA bases, which generates additional saturated, sixmembered ring in a DNA base. These adducts are derived from the reaction of DNA with, e.g., acrolein, crotonaldehyde and HNE. AcrdG, Cro-dG and HNE-dG were found in rodent and human tissues [51,52]. Etheno DNA adducts posses five-membered exocyclic rings attached to DNA bases. The exact pathway of their formation in vivo is not known, although it is clear that they are generated by the exposition of DNA to lipid peroxides. Ethenoadducts are also introduced into DNA by certain environmental carcinogens like vinyl chloride or its metabolite, chloroacetaldehyde (CAA) [53]. Propanoand etheno-type adducts that are found in native mammalian DNA are unsubstituted and substituted with side chains of different length, depending on the structure of reacting LPO product. All exocyclic DNA adducts have strong miscoding potential. Unsubstituted exocyclic DNA adducts are more mutagenic than toxic. With the increase of the side chain the toxic properties increase and are related to the inhibition of replication and transcription [54,55]. Elevated levels of ␧dA and ␧dC were found in pro-carcinogenic colon diseases, like inflammatory bowel disease, Crohn’s disease and ulcerative colitis, and in addition in chronic pancreatitis [20,56]. This suggests that LPO-derived DNA lesions contribute to CRC etiology.

4. Repair of oxidative DNA damage as a driving force to colon carcinogenesis The major pathway for repair of oxidatively derived DNA lesions is base excision repair system (BER). Although several oxidatively damaged bases are also repaired by mismatch repair system and AlkB family dioxygenases, this review will focus on BER activity. In a classical view BER consists of five steps: (i) lesion recognition, (ii) excision of the damaged base, (iii) AP site incision and removal of the chemical residues that could block further steps of the pathway, (iv) incorporation of the proper nucleotide(s) by DNA polymerases and (v) ligation of the DNA strand to restore the original DNA molecule [57–60]. Damaged bases are recognized by DNA glycosylases, which excise from DNA a wide range of oxidized and alkylated bases. Presently, 13 human DNA glycosylases with different, but partially overlapping substrate specificity have been identified. Mechanistically two types of DNA glycosylases can be distinguished, monofunctional enzymes, that excise damaged base leaving behind an abasic (AP) site, which is subsequently cleaved by AP endonuclease (APE1) 5 to the AP site, and bifunctional DNA glycosylases, which have endowed AP lyase activity that incises phosphodiester bonds 3 to the AP site created by the glycosylase activity of the enzyme. This review will focus on repair of three oxidative DNA lesions, 8-oxoGua, ␧Ade and ␧Cyt. 8-OxoGua is repaired by a three-step system, which (i) limits incorporation of 8-oxodGTP into DNA during replication, (ii) excises 8-oxoGua from DNA, and (iii) corrects the base opposite to 8-oxoGua in DNA. Different DNA polymerases can incorporate 8oxodGTP to the DNA, and replicative DNA polymerases incorporate this modified nucleotide usually opposite dA, generating A:T → C:G mutations. Approximately a half of 8-oxodG in DNA arises from the direct DNA oxidation, and the other half is a result of incorporation of 8-oxodGTP during DNA synthesis. Incorporation of 8-oxodGTP into DNA by DNA polymerases is limited by the activity of MTH1 phosphohydrolase, which hydrolyzes 8-oxodGTP to 8-oxodGMP [61]. 8-OxodGMP is subsequently dephoshorylated by nucleotidase and removed from the cell [62]. Many observations indicate a direct correlation between 8-oxodG formation and carcinogenesis

86

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92

in vivo [46,63–66]. The second line of defence is glycosylase MutY (MYH) that removes adenine paired with 8-oxoGua. Activity of this enzyme prevents mutations G:C → T:A, when dATP is incorporated opposite 8-oxoGua during replication [67]. After removal of Ade by MYH glycosylase, repair DNA polymerase incorporates dCMP opposite 8-oxodG. Then 8-oxoGua can be excised by the third component of the system, OGG1 glycosylase [68]. OGG1 glycosylase/AP lyase is the major enzyme catalyzing excision of 8-oxoGua from DNA, but only when paired with Cyt or Thy [69,70]. The AP lyase activity of the OGG1 protein is about 10-fold lower than that of the glycosylase [71]. When 8-oxodGTP is included into DNA during replication it is probably removed by NEIL1 or NEIL2 glycosylases, which excises 8-oxoGua paired with dC/G/T/A or dC/A, respectively [72]. This complex three-tier system prevents mutations induced by the presence of 8-oxodG in DNA, both when this lesion is induced directly in the DNA, and when it is incorporated from the pool of nucleotides during replication. Polymorphisms of MYH and OGG1 glycosylases are related to modulation of susceptibility to colon cancer. MYH variations significantly increase CRC risk, and of several mutations described, two are the most prevalent: Y165C (exon 7) and G382D (exon 13). Mutated enzyme excises Ade from dA:8-oxodG pair with a decreased rate, increasing mutation frequency. The association of MYH with CRC was first reported in 2002 [73]. Several polymorphic changes in the OGG1 gene have been described, with the most common being Ser326Cys [74]. Polymorphic Cys326 OGG1 protein was found to have a lower enzymatic activity, both when 8-oxoGua was excised from oligodeoxynucleotides [75], and when 8-oxoGua and FapyGua were liberated from ␥-irradiated DNA by purified Cys326 or Ser326 OGG1 enzyme [74,76]. It was suggested that the presence of two OGG1 326Cys alleles may confer an increased risk of lung, prostate and nasopharyngeal cancer [77–79], but no association with the risk for colon cancer was found [80,81]. Our and other functional studies report a decrease in 8-oxoGua excision rate in lung [41,82,83] and head and neck cancer patients [84]. Such a decrease in excision rate and simultaneous increase in 8-oxodG and FapydG levels in cellular DNA favors a pro-oxidant state and may accelerate the acquisition of mutations in critical genes leading to cancer. Such an idea is basically derived from the observation that a pro-oxidant environment is characteristic for advanced stages of cancer. ␧Ade is excised by alkylpurine-DNA-N-glycosylase (ANPG) [85], whereas ␧Cyt by thymine-DNA glycosylase (TDG); the latter also excises thymine from G:T pairs, resulting from deamination of 5-methylcytosine [86]. Ethenocytosine is also excised by singlestranded uracil DNA glycosylase, SMUG1 [87] and by MBD4 glycosylase, although activity of the latter is strongly limited to CpG islands [88,89]. ANPG glycosylase has a wide substrate specificity, and besides ␧Ade excises from DNA also 1,N2 -ethenoguanine [90], hypoxanthine and the alkylated bases, 3-methyladenine and 7methylguanine [85]. TDG excises ␧Cyt, Thy and Ura from pairs with guanine, and its activity is strongly stimulated by the next enzyme in the BER pathway, AP endonuclease, APE1 [91]. TDG and APE1 also play the role of transcription regulators [92–95]. Ethenocytosine repair by the BER system is dependent not only on the level and activity of TDG, MBD4 or SMUG1 DNA glycosylases, but also on the presence and/or activity of ANPG glycosylase, which primary substrate is ␧Ade. ANPG binds strongly to DNA containing ␧Cyt, and although does not excise this modified base, does not allow its excision by the proper ␧Cyt glycosylase, like TDG [96]. This may explain observation that the level of ␧Cyt measured in different human tissues was constantly higher than that of ␧Ade [19].

Table 1 mRNA level of DNA glycosylases (OGG1, ANPG and TDG) and APE endonuclease (APE1), and MTH1 phosphohydrolase in relation to 18S rRNA (×10−6 ) in leukocytes of CRC and AD patients and healthy controls. mRNA level (arbitrary units)a

OGG1

ANPG

TDG

APE1

MTH1

p

CRC patients (C)

AD patients (A)

Controls (H)

1.28 (0.71–5.58) n = 44 12.14 (4.06–37.07) n = 44 7.97 (1.87–21.03) n = 44 88.25 (42.88–362.51) n = 44 86.82 (5.19–728.53) n = 37

0.99 (0.45–4.91) n = 38 –

0.19 (0.06–0.54) n = 40 1.08 (0.31–4.75) n = 39 0.81 (0.26–1.84) n = 39 13.87 (2.32–43.04) n = 40 5.26 (0.33–11.69) n = 19

–

113.83 (48.74–292.37) n = 38 –

<0.001 (C vs. H)b <0.001 (A vs. H)b 0.46 (C vs. A)b <0.001(C vs. H)

<0.001 (C vs. H)

<0.001 (C vs. H)b <0.001 (A vs. H)b 0.5 (C vs. A)b 0.0012 (C vs. H)

Adapted from [42,105] with permission from Oxford University Press and Elsevier, respectively. All subjects were Caucasians. a Comparison of mRNA levels, expressed as median and interquartile range, between CRC and AD patients and controls (Mann–Whitney U test). b p values are after Bonferroni correction.

4.1. Repair of 8-oxo-7,8-dihydro-2 -deoxyguanosine in colon adenoma and carcinoma patients In order to get an insight into the importance of oxidative stress and repair of oxidatively damaged DNA bases in the pathology of colon cancer, we examined groups of individuals at different stages of disease development, namely CRC patients, patients who developed benign adenomas (AD) and healthy individuals for the markers of oxidative stress, repair capacity of oxidatively damaged DNA, and polymorphism of DNA repair genes. Increased oxidative stress was observed both in CRC patients and in AD individuals. This manifested in an elevation of the 8oxodG level in leukocyte DNA and in urine as well as depletion of antioxidant vitamins (ascorbic acid, ␣-tocopherol, retinol) and uric acid in blood plasma of CRC patients and AD individuals in comparison to healthy controls [42]. Depletion of antioxidant vitamins in blood plasma was gradual, which suggests that oxidative stress is increasing gradually with the disease progression. This is supported by the fact that urinary level of 8-oxodG was augmented already in AD patients, but 8-oxoGua level was enhanced only in CRC, but not in AD individuals [42]. Urinary 8-oxodG may reflect oxidation of nucleotide pool, while 8-oxoGua reflects rather oxidation of DNA. Since nucleotide pool is much more susceptible to oxidation than dsDNA, 8-oxodG in urine may be a more sensitive indicator of oxidative processes in the body, and shows that even in AD individuals the oxidative processes are enhanced. The suggested mechanisms responsible for the oxidative stress in cancer patients include [43]: (i) granulocyte activation with release of ROS; (ii) stimulation of cytokines, of which some, e.g., tumor necrosis factor, produce large amounts of ROS; (iii) production of hydrogen peroxide by malignant cells, which in advanced stages of cancer may be released into the blood stream and penetrate into other tissues [2]. Interestingly, we also observed an increase of mRNA levels of repair enzymes, OGG1, APE1 and MTH1 in leukocytes of CRC and AD individuals (Table 1) [42]. Expression of APE1 and OGG1 genes was shown to be induced by ROS [97], and this could explain induction of repair enzymes transcription in leukocytes of CRC and AD individuals. On the other hand induction of repair enzymes may be a part of a carcinogenic program, which might decrease apoptosis

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92

A

100

CRC patients Controls

8-oxoGua excision activity (pmols/h/mg protein)

90 80

***

70 60

n = 68

50 40

n = 90

30 20 10 0

B

120

8-oxoGua excision activity (pmols/h/mg protein)

110

***

CRC patients Controls

100

* **

90 80 70

n = 34

60

n = 14

50 40

n = 53

30

n = 13

n = 32

20 10 0 Ser/Ser

Ser/Cys

Cys/Cys

OGG1 Ser326Cys polymorphism Fig. 2. The mean and standard deviation of 8-oxoGua excision activity in leukocytes of CRC patients and control individuals, in the entire groups (A) and in the groups distinguished on the basis of OGG1 Ser326Cys polymorphism (B). ***, p < 0.001; **, p < 0.005; *, p < 0.05 (Mann–Whitney U test). Adapted from [42] with permission from Oxford University Press.

in aberrant cells and/or favor genomic instability. Our results corroborate the findings of Winnepenninckx and coworkers [98] that induction of most of the DNA repair genes occurs very early in the carcinogenic process, e.g., four years before clinical manifestation of malignant skin melanoma. Increase of mRNA level of OGG1 and APE1 repair enzymes was accompanied by the augmentation of 8-oxoGua excision rate in leukocytes of CRC patients (Fig. 2A) [42]. The higher activity observed in the cell extracts from the cancer patients is even more meaningful in view of the finding that homozygous OGG1 326Cys variants, which are generally characterized by lower OGG1 activity,

87

were much more frequent among the cancer patients than in the control and adenoma groups (Table 2) [42]. In our study the effect of the OGG1 Ser326Cys polymorphism on 8-oxoGua excision rate was clearly seen in the CRC patient group, in which Cys homozygotes were found to have a decreased 8-oxoGua excision rate in comparison with Ser homozygotes (Fig. 2B) [42]. Thus, the observed increase in 8-oxoGua repair capacity in CRC patients in comparison to healthy individuals might be due to increased transcription from OGG1 and APE1 genes, which was observed in AD and CRC individuals (Table 1) [42]. Interestingly, the OGG1 genotype exerted a limited effect on 8-oxodG level in leukocytes and urinary excretion of 8-oxoGua [42]. In contrast to our studies, Janssen et al. [99] and Jensen et al. [100] reported that 8-oxoGua repair incision in human lymphocytes was unaffected by the polymorphic status at codon 326 of the OGG1 gene. These studies were performed on the population of healthy subjects only. It was shown that OGG1 Cys326 variant forms dimers with lower enzymatic activity only under conditions of oxidative stress probably due to OGG1 cysteine 326 oxidation [101]. In parallel, Bravard et al. [102] reported recently that extracts from lymphoblastoid cell lines established from individuals carrying the Cys326Cys genotype have almost 2-fold lower basal 8-oxoGua DNA glycosylase activity than the Ser326Ser variant and were more sensitive to inactivation by oxidizing agents than that of the Ser/Ser cells. Analysis of redox status of the OGG1 protein in cells confirmed that the lower activity of OGG1-Cys326 was associated with the oxidation of Cys326 to form a disulfide bond. Thus different degrees of oxidative stress in different studies might partially explain the controversies in the literature. In the group of healthy subjects there was significant positive correlation between mRNA levels of the main enzymes involved in 8-oxoGua removal (OGG1 and APE1), and the amount of 8-oxoGua in urine [42]. These findings suggested that the amount of 8-oxoGua in urine might be attributed to DNA repair. It is in parallel with previous results, which also showed that DNA repair was responsible for the presence of oxidatively damaged DNA lesions in urine [103]. However, we did not find such correlation in the groups of adenoma individuals and carcinoma patients. The main reason for this inconsistency may be aberrant DNA oxidation in cancerous and precancerous conditions which may overshadow the subtle relationship observed in healthy subjects. Alternatively, the excretion of 8-oxoGua might reflect the level of oxidative stress, independent of the activities of the repair enzymes [104]. Also, only a weak positive correlation was found between 8oxoGua level in urine and the stage of disease [42]. 4.2. Repair of etheno DNA adducts in colon carcinogenesis In contrast to cleavage of 8-oxoGua, leukocytes excision activity of ␧Ade and ␧Cyt was significantly lower in CRC patients when

Table 2 Genotypes and allelic frequencies of the OGG1 Ser326Cys polymorphism among CRC patients, individuals with AD and healthy controls. OGG1 polymorphism Ser326Cys Ser/Ser Ser/Cys Cys/Cys Allelic frequency Ser (C) Cys (G)

CRC patients (C)(n = 74)a n (%)

AD patients (A)(n = 76)a n (%)

Controls (H)(n = 97)a n (%), (%)b

p

38 (51.3) 19 (25.7) 17 (23)

46 (60.5) 29 (38.2) 1 (1.3)

63 (65), (81)c 33 (34), (18)d 1 (1), (1)e

>0.0000 (C vs. H) >0.079 (A vs. H) >0.0000 (C vs. A)

0.64 0.36

0.8 0.2

0.82 0.18

Adapted from [42] with permission from Oxford University Press. All subjects were Caucasians. a Comparison of OGG1 polymorphic frequency between CRC and AD patients and controls (Chi-square distribution analysis). b Results from Hardy–Weinberg equilibrium. c Homozygous OGG1 Ser326Ser individuals. d Heterozygous OGG1 Ser326Cys individuals. e Homozygous OGG1 Cys326Cys individuals.

88

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92

A

50 45

***

CRC patients Controls

Excision activity (pmols/h/μg protein)

40

n = 56

35 30 25

n = 54

20 15

*

10

n = 54

5

n = 56

0

Excision activity (pmols/h/μg protein)

B

εAde

εCyt

16

***

14

Tumor Normal colon

n = 54

12 10

***

8

n = 54

6

n = 54

4

n = 54 2 0

εAde

εCyt

Fig. 3. (A) The mean and standard deviation of ␧Ade and ␧Cyt excision rate in leukocyte DNA of CRC patients and control individuals. ***, p < 0.001; *, p < 0.05 (Mann–Whitney U test). (B) The mean and standard deviation of ␧Ade and ␧Cyt excision rate in colon tumor and normal surrounding tissues of CRC patients. ***, p < 0.001 (Wilcoxon rank sum test). Derived from [105] with permission from Elsevier.

compared to controls matched for age, sex and a smoking habit (Fig. 3A) [105]. However, in colon tissues, excision activities for ␧Ade and ␧Cyt were significantly higher in tumor than in adjacent, asymptomatic colon tissue (Fig. 3B) [105]. In leukocytes (PBL) of CRC patients ␧dA and 1,N2 -␧dG level was unexpectedly lower than in controls, and the level of ␧dA and ␧dC also showed a tendency to be lower in tumor than in normal colon tissue [105]. This suggests that the regulation of etheno adduct level and repair may be multifactorial and may differ in target (colon) and surrogate (PBL) tissues. The lower excision rate for ␧Ade and ␧Cyt in leukocytes of CRC patients was not linked to mutations in exons of ANPG and TDG genes nor to down regulation of mRNA expression of ANPG and TDG glycosylases or its BER activator, APE1 endonuclease; in the contrary, mRNA levels of these repair enzymes were significantly higher in PBL of CRC than in healthy controls (Table 1) [42,105]. Thus direct inactivation/inhibition of repair enzymes activities by inflammatory mediators released in the blood stream is a more likely explanation. Indeed, several DNA repair enzymes were shown to be directly inhibited by nitric oxide [106–108], hydrogen peroxide [109] and LPO product, 4-hydroxynonenal [55,110]. As shown for several human cancer sites and animal tumors, persistent oxidative stress and LPO-induced DNA damage increased already during premalignant stages in a time-dependent manner [111]. A number of studies demonstrated increase of mRNA level of several repair enzymes upon oxidative stress [97,112,113]. The observed lower ␧Ade and ␧Cyt excision (Fig. 3A) and simultaneous lower level of etheno adducts in PBL of cancer patients [105]

may thus suggest that other mechanisms are up-regulated in CRC patients and determine the level of etheno adducts in DNA. Other repair systems engaged in etheno adducts elimination from DNA include, e.g., oxidative demethylation by AlkB family proteins or nucleotide excision repair [114,115]. Of interest are the findings in tumorous colon tissue. The ␧Ade and ␧Cyt excising activities were much higher in tumor than in the surrounding normal colon (Fig. 3B) and was consistent with a 2–3 times lower ␧dA and ␧dC adduct levels [105]. Also in several other studies lower level of ␧dA and ␧dC was observed in colon tumors than in colon tissues of cancer prone patients suffering from ulcerative colitis, Crohn’s disease or familial adenomatous polyposis [56,116]. In our study in normal colon a negative correlation was found between ␧dC level in DNA and its excision rate ( = −0.64, p = 0.013) [105]. This supports a role of BER in ␧Cyt-elimination; however, does not exclude other etheno adduct control systems. In several types of non tumorous human tissues previously analyzed, the ␧dA level in DNA was found to be lower than that of ␧dC [111], consistent with our observation that excision activity was found to be higher for ␧Ade than for ␧Cyt (Fig. 3) [105]. In order to understand a huge increase of excision activity of ␧Ade and ␧Cyt in colon tumor tissue in comparison to asymptomatic colon margin, we measured mRNA level of ANPG and TDG glycosylases, as well as APE1 endonuclease in tumor and normal colon tissues. Higher mRNA level in tumor tissue was observed only for APE1 [105]. APE1 stimulates ␧Cyt excision [91], and most probably also ␧Ade. Another possibility are frequent mutations in the APC gene in colon tumors [117]. APC tumor suppressor protein may inhibit BER engaged in repair of ␧Ade and ␧Cyt since it was shown that it can directly interact with DNA polymerase ␤ and FEN1 endonuclease [118]. BER activity was inversely associated with APC expression in several breast cancer cell lines [119]. In conclusion, we have shown, for the first time, that excision activity of ␧Ade and ␧Cyt is lower in PBL of CRC patients when compared to healthy individuals. However, our unexpected findings, that the level of ␧dA and 1,N2 -␧dG was lower in DNA of PBL from CRC patients than in healthy controls currently remains mechanistically difficult to explain. If such etheno adducts, particularly ␧Cyt excision deficiency also occurs during premalignant stages in the target organ, still may favor acquisition of mutations in critical genes leading to neoplastic transformation. TDG glycosylase removes Thy and Ura paired with guanine, and may prevent induction of mutations caused by cytosine and 5-methylcytosine deamination [120].

5. Aberrant repair of oxidatively damaged DNA bases and mutations in critical genes Activity and expression of BER proteins is modulated by two signaling molecules, which are frequently mutated in colon cancer, the APC and TP53 gene products. Thus, mutations in these genes affect repair rate of oxidatively damaged DNA, and favor pro-mutagenic events within colon epithelial cells. On the other hand at least three BER proteins, namely, APE1, TDG and OGG1 take part in the regulation of gene expression. Mutations in the APC gene are early events in colon carcinogenesis, and are found in about 80% of colon adenomas and carcinomas. The most frequent mutation results in truncation of the C-terminal part of the APC protein. Wild type APC protein directly interacts with DNA polymerase ␤, FEN1 endonuclease [118], and as recently suggested, APE1 endonuclease [121] inhibiting the assembly of BER proteins on damaged DNA and the activity of short and long patch BER (Fig. 4). In LoVo, colon cancer cells expressing truncated APC protein an accelerated assembly of BER proteins, as well as higher activity of APE1, FEN1 and Pol ␤ were observed [121]. Activation of

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92

Progression

Genome instability

APE1/ ANPG

+ APC mutated

+

TDG/MBD4

+

AID-mediated demethylation of gene promoters

Transcription of several genes

+ +

Angiogenesis Erythropoesis

Progression

+

Pol β FEN1 APE1

TP53 mutated

Genome instability

89

+

HIF-1α

OGG1

Transcription of Myc-regulated genes

Proliferation Progression

Fig. 4. The influence of APC and TP53 genes mutations on the activity of BER enzymes and genome stability. Mutations in APC and TP53 proteins lead to increase in APE1 activity and transcription, respectively, and up-regulate BER. Increased APE1, ANPG and unbalanced BER pathway may favor genomic instability and cancer progression. APE1 activity may also accelerate the excision rate of DNA glycosylases, OGG1 and TDG/MBD4. APE1, TDG and OGG1 take part in the regulation of gene expression. TDG interacts with the deaminase AID and may favor demethylation of promoters and induction of transcription of several genes. OGG1 and APE1 stimulate transcription of genes regulated by c-Myc and estrogen receptors, and thus may contribute to acceleration of cell proliferation. Increased APE1 activity may result in unbalancing of BER pathway, and may favor genomic instability and cancer progression. APE1 also participates in HIF-1␣ mediated angiogenesis and erythropoesis and may favor tumor growth. + symbol in circle denotes stimulation or increase; APC, adenomatous polyposis coli; Pol ␤, DNA polymerase ␤; FEN 1, flap endonuclease 1; APE1, apurinic site endonuclease 1; ANPG, alkyladenine DNA N-glycosylase; OGG1, 8-oxoGua DNA N-glycosylase; TDG, thymine DNA N-glycosylase; MBD4, methyl-CpG binding domain protein; AID, activation-induced deaminase; HIF-1␣, hypoxia-inducible factor 1␣ subunit.

APE1 may also occur as a consequence of TP53 gene mutations, which are late, but frequent events in colon carcinogenesis (in about 50% of cancers). TP53 protein participates in downregulation of APE1 transcription in cells treated with DNA damaging agents [122]. On the other hand TP53 mediates ubiquitination of APE1 by TP53 inhibitor, MDM2, and in consequence APE1 degradation [123]. Thus, mutations in TP53 gene should additionally increase APE1 amount in cancer cells. Increased APE1 activity may result in unbalancing of BER pathway, and may favor genomic instability and cancer progression: in inflamed non-cancerous colon tissues of ulcerative colitis patients (at high risk for colon cancer, that accumulate high etheno DNA adducts [124]), ANPG and APE1 activities were significantly increased, and microsatellite instability (MSI) was positively correlated with their imbalanced activities of repair enzymes [125]. Similarly, in yeast and human cells over-expression of ANPG and/or APE1 was associated with frameshift mutations and MSI [125]. APE1, besides DNA repair function, also plays a role of redox regulatory protein for several transcription factors. For example, participates in HIF-1␣ mediated angiogenesis [126]. Thus at late stages of CRC development, mutations in TP53 gene will lead to accumulation of APE1 protein, and in addition to increasing genome instability will also favor angiogenesis and in consequence tumor growth (Fig. 4). Increased APE1 activity may also accelerate the excision rate of DNA glycosylases. TDG and OGG1 were shown to be particularly susceptible to induction by APE1, since they bind strongly to AP sites, and APE1 increases turnover of these enzymes on damaged DNA [91,127]. Increased activity of TDG may favor demethylation of promoters of several genes and in consequence contribute to hypomethylation of DNA observed in colon cancer [13] and induction of transcription of several genes. TDG interacts with the deaminase AID and the damage response protein GADD45a. 5Methylcytosine and 5-hydroxymethylcytosine are first deaminated by AID to thymine and 5-hydroxymethyluracil, respectively, and subsequently TDG removes thymine and 5-hydroxymethyluracil from dT:dG or 5OHMedU:dG pairs, which initiates BER and enables reconstitution of G:C base pairs [128]. TDG is also necessary for recruiting p300 to retinoic acid (RA)-regulated promoters, and is engaged in transcriptional control of genes during embryonic

development. Its deficiency is embrionaly lethal [120]. TDG status may also determine sensitivity of CRC patients to chemotherapy with 5-fluorouracil (5-FU), a chemotherapeutic routinely used in CRC treatment. Inactivation of TDG significantly increases resistance of mouse and human cancer cells toward 5-FU. Excision of 5-FU from DNA by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling. Hence, excision of 5-FU by TDG mediates DNA-directed cytotoxicity [129]. OGG1 and APE1 stimulate transcription of genes regulated by c-Myc transcription factor [130], and thus may contribute to acceleration of cell proliferation (Fig. 4). The mechanism involves demethylation of histone H3 by specific FAD-containing enzyme, LSD1 demethylase which generates hydrogen peroxide during demethylation [131]. In consequence a local oxidation of DNA around the E-boxes and TSS region of Myc target genes is triggered. 8-OxodG, OGG1 and APE1 were found to be engaged on the same RNA polymerase II and Myc occupied chromatin regions of Myc targets and stimulate transcription of these genes. Silencing of either OGG1 or APE1 inhibits Myc mediated transcription. It is possible that regulatory regions in a gene interact with each other forming loops that often bridge considerable distances on the genomic loci [132]. Following Myc binding local demethylation of lysine 4 in histone H3 (H3K4me2) triggers recruitment of the OGG1 and the downstream BER enzymes thus producing nicks on Myc target chromatin. This may relax the DNA strands and could favor chromatin bending necessary for the formation of chromatin loops that bring together RNAPII and Myc. OGG1 is also engaged in the regulation of transcription from estrogen promoters [133]. 6. Conclusions Oxidative stress is induced at the early, adenoma, stage of colon carcinogenesis, and is increasing during disease progression. CRC and AD patients reveal a huge increase of mRNA level of base excision repair enzymes in blood leukocytes. However, increased transcription is not always correlated with repair capacity of tissues. Activities of BER enzymes remain under a complex regulative network, which besides stimulation of transcription includes direct inactivation by oxidation stress products, interaction with other

90

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92

BER proteins, and with signaling molecules, which are frequently mutated in colon cancer, that is APC and TP53 proteins. Mutated proteins do not inhibit transcription and/or activity of base excision repair enzymes. This increases the amount of repair enzymes within cells and introduces imbalance in the repair of oxidative DNA damage. Such imbalance causes increased genome instability and may be a driving force in the disease progression. Conflict of interest statement The authors declare that there are no conflicts of interest. Funding Funded by the Polish-French grant project 346/N-INCA/2008/0. We thank all patients and volunteers who participated in this study. References [1] F. Levi, C. Pasche, C. La Vecchia, F. Lucchini, S. Franceschi, Food groups and colorectal cancer risk, Br. J. Cancer 79 (1999) 1283–1287. [2] M. Dizdaroglu, R. Olinski, J.H. Doroshow, S.A. Akman, Modification of DNA bases in chromatin of intact target human cells by activated human polymorphonuclear leukocytes, Cancer Res. 53 (1993) 1269–1272. [3] G. Bouguen, S. Manfredi, M. Blayau, C. Dugast, B. Buecher, D. Bonneau, L. Siproudhis, V. David, J.F. Bretagne, Colorectal adenomatous polyposis associated with MYH mutations: genotype and phenotype characteristics, Dis. Colon Rectum 50 (2007) 1612–1617. [4] S. Jones, P. Emmerson, J. Maynard, J.M. Best, S. Jordan, G.T. Williams, J.R. Sampson, J.P. Cheadle, Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C → T:A mutations, Hum. Mol. Genet. 11 (2002) 2961–2967. [5] V. Gismondi, M. Meta, L. Bonelli, P. Radice, P. Sala, L. Bertario, A. Viel, M. Fornasarig, A. Arrigoni, M. Gentile, M. Ponz de Leon, L. Anselmi, C. Mareni, P.L. Bruzzi, Varesco prevalence of the Y165C, G382D and 1395GGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas, Int. J. Cancer 109 (2004) 680–684. [6] B.R. Berquist, D.M. Wilson, 3rd pathways for repairing and tolerating the spectrum of oxidative DNA lesions, Cancer Lett. (2012). [7] B. Tudek, A. Winczura, J. Janik, A. Siomek, M. Foksinski, R. Olinski, Involvement of oxidatively damaged DNA and repair in cancer development and aging, Am. J. Transl. Res. 2 (2010) 254–284. [8] M.S. Cooke, R. Olinski, M.D. Evans, Does measurement of oxidative damage to DNA have clinical significance? Clin. Chim. Acta 365 (2006) 30–49. [9] S. Maynard, S.H. Schurman, C. Harboe, N.C. de Souza-Pinto, V.A. Bohr, Base excision repair of oxidative DNA damage and association with cancer and aging, Carcinogenesis 30 (2009) 2–10. [10] S.E. Kent, B. Majumdar, Metastatic tumours in the maxillary sinus. A report of two cases and a review of the literature, J. Laryngol. Otol. 99 (1985) 459–462. [11] B. Tudek, R.P. Bird, W.R. Bruce, Foci of aberrant crypts in the colons of mice and rats exposed to carcinogens associated with foods, Cancer Res. 49 (1989) 1236–1240. [12] B.A. Magnuson, I. Carr, R.P. Bird, Ability of aberrant crypt foci characteristics to predict colonic tumor incidence in rats fed cholic acid, Cancer Res. 53 (1993) 4499–4504. [13] E.R. Fearon, Molecular genetics of colorectal cancer, Annu. Rev. Pathol. 6 (2011) 479–507. [14] M. van de Wetering, E. Sancho, C. Verweij, W. de Lau, I. Oving, A. Hurlstone, K. van der Horn, E. Batlle, D. Coudreuse, A.P. Haramis, M. Tjon-Pon-Fong, P. Moerer, M. van den Born, G. Soete, S. Pals, M. Eilers, R. Medema, H. Clevers, The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells, Cell 111 (2002) 241–250. [15] M. Valko, C.J. Rhodes, J. Moncol, M. Izakovic, M. Mazur, Free radicals, metals and antioxidants in oxidative stress-induced cancer, Chem. Biol. Interact. 160 (2006) 1–40. [16] M. Valko, D. Leibfritz, J. Moncol, M.T. Cronin, M. Mazur, J. Telser, Free radicals and antioxidants in normal physiological functions and human disease, Int. J. Biochem. Cell Biol. 39 (2007) 44–84. [17] L.A. Loeb, Cancer cells exhibit a mutator phenotype, Adv. Cancer Res. 72 (1998) 25–56. [18] K.B. Beckman, B.N. Ames, Oxidative decay of DNA, J. Biol. Chem. 272 (1997) 19633–19636. [19] H. Bartsch, J. Nair, Oxidative stress and lipid peroxidation-derived DNAlesions in inflammation driven carcinogenesis, Cancer Detect. Prev. 28 (2004) 385–391. [20] J. Potack, S.H. Itzkowitz, Colorectal cancer in inflammatory bowel disease, Gut Liver 2 (2008) 61–73. [21] K. Uchida, 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress, Prog. Lipid Res. 42 (2003) 318–343.

[22] F.L. Chung, R.G. Nath, M. Nagao, A. Nishikawa, G.D. Zhou, K. Randerath, Endogenous formation and significance of 1,N2-propanodeoxyguanosine adducts, Mutat. Res. 424 (1999) 71–81. [23] F.L. Chung, J. Pan, S. Choudhury, R. Roy, W. Hu, M.S. Tang, Formation of trans-4hydroxy-2-nonenal- and other enal-derived cyclic DNA adducts from omega3 and omega-6 polyunsaturated fatty acids and their roles in DNA repair and human p53 gene mutation, Mutat. Res. 531 (2003) 25–36. [24] H.J. Chen, F.L. Chung, Epoxidation of trans-4-hydroxy-2-nonenal by fatty acid hydroperoxides and hydrogen peroxide, Chem. Res. Toxicol. 9 (1996) 306–312. [25] C.E. Eberhart, R.J. Coffey, A. Radhika, F.M. Giardiello, S. Ferrenbach, R.N. DuBois, Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas, Gastroenterology 107 (1994) 1183–1188. [26] H. Sano, Y. Kawahito, R.L. Wilder, A. Hashiramoto, S. Mukai, K. Asai, S. Kimura, H. Kato, M. Kondo, T. Hla, Expression of cyclooxygenase-1 and -2 in human colorectal cancer, Cancer Res. 55 (1995) 3785–3789. [27] M.J. Thun, S.J. Henley, C. Patrono, Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues, J. Natl. Cancer Inst. 94 (2002) 252–266. [28] C.H. Liu, S.H. Chang, K. Narko, O.C. Trifan, M.T. Wu, E. Smith, C. Haudenschild, T.F. Lane, T. Hla, Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice, J. Biol. Chem. 276 (2001) 18563–18569. [29] D. Wang, R.N. Dubois, Prostaglandins and cancer, Gut 55 (2006) 115–122. [30] M.A. Iniguez, A. Rodriguez, O.V. Volpert, M. Fresno, J.M. Redondo, Cyclooxygenase-2: a therapeutic target in angiogenesis, Trends Mol. Med. 9 (2003) 73–78. [31] A. Greenhough, H.J. Smartt, A.E. Moore, H.R. Roberts, A.C. Williams, C. Paraskeva, A. Kaidi, The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment, Carcinogenesis 30 (2009) 377–386. [32] N. Speed, I.A. Blair, Cyclooxygenase- and lipoxygenase-mediated DNA damage, Cancer Metastasis Rev. 30 (2011) 437–447. [33] B.S. Reddy, C.V. Rao, Novel approaches for colon cancer prevention by cyclooxygenase-2 inhibitors, J. Environ. Pathol. Toxicol. Oncol. 21 (2002) 155–164. [34] A. Strillacci, C. Griffoni, M.C. Valerii, G. Lazzarini, V. Tomasi, E. Spisni, RNAi-based strategies for cyclooxygenase-2 inhibition in cancer, J. Biomed. Biotechnol. (2010) 828045. [35] S. Ishikawa, S. Tamaki, M. Ohata, K. Arihara, M. Itoh, Heme induces DNA damage and hyperproliferation of colonic epithelial cells via hydrogen peroxide produced by heme oxygenase: a possible mechanism of heme-induced colon cancer, Mol. Nutr. Food Res. 54 (2010) 1182–1191. [36] J.P. Angeli, C.C. Garcia, F. Sena, F.P. Freitas, S. Miyamoto, M.H. Medeiros, P. Di, Mascio lipid hydroperoxide-induced and hemoglobin-enhanced oxidative damage to colon cancer cells, Free Radic. Biol. Med. 51 (2011) 503–515. [37] H.K. Seitz, P. Becker, Alcohol metabolism and cancer risk, Alcohol Res. Health 30 (38–41) (2007) 37–44. [38] C.C. Garcia, J.P. Angeli, F.P. Freitas, O.F. Gomes, T.F. de Oliveira, A.P. Loureiro, P. Di Mascio, M.H. Medeiros, [13C2]-Acetaldehyde promotes unequivocal formation of 1,N2-propano-2 -deoxyguanosine in human cells, J. Am. Chem. Soc. 133 (2011) 9140–9143. [39] E. Eder, M. Wacker, P. Wanek, Lipid peroxidation-related 1,N2propanodeoxyguanosine-DNA adducts induced by endogenously formed 4-hydroxy-2-nonenal in organs of female rats fed diets supplemented with sunflower, rapeseed, olive or coconut oil, Mutat. Res. 654 (2008) 101–107. [40] Y. Wang, G. Millonig, J. Nair, E. Patsenker, F. Stickel, S. Mueller, H. Bartsch, H.K. Seitz, Ethanol-induced cytochrome P4502E1 causes carcinogenic ethenoDNA lesions in alcoholic liver disease, Hepatology 50 (2009) 453–461. [41] D. Gackowski, E. Speina, M. Zielinska, J. Kowalewski, R. Rozalski, A. Siomek, T. Paciorek, B. Tudek, R. Olinski, Products of oxidative DNA damage and repair as possible biomarkers of susceptibility to lung cancer, Cancer Res. 63 (2003) 4899–4902. [42] T. Obtulowicz, M. Swoboda, E. Speina, D. Gackowski, R. Rozalski, A. Siomek, J. Janik, B. Janowska, J.M. Ciesla, A. Jawien, Z. Banaszkiewicz, J. Guz, T. Dziaman, A. Szpila, R. Olinski, B. Tudek, Oxidative stress and 8-oxoguanine repair are enhanced in colon adenoma and carcinoma patients, Mutagenesis 25 (2010) 463–471. [43] R. Olinski, D. Gackowski, R. Rozalski, M. Foksinski, K. Bialkowski, Oxidative DNA damage in cancer patients: a cause or a consequence of the disease development? Mutat. Res. 531 (2003) 177–190. [44] R. Olinski, D. Gackowski, M. Foksinski, R. Rozalski, K. Roszkowski, P. Jaruga, Oxidative DNA damage: assessment of the role in carcinogenesis, atherosclerosis, and acquired immunodeficiency syndrome, Free Radic. Biol. Med. 33 (2002) 192–200. [45] M.D. Evans, M. Dizdaroglu, M.S. Cooke, Oxidative DNA damage and disease: induction, repair and significance, Mutat. Res. 567 (2004) 1–61. [46] P. Jaruga, T.H. Zastawny, J. Skokowski, M. Dizdaroglu, R. Olinski, Oxidative DNA base damage and antioxidant enzyme activities in human lung cancer, FEBS Lett. 341 (1994) 59–64. [47] K.C. Cheng, D.S. Cahill, H. Kasai, S. Nishimura, L.A. Loeb, 8-Hydroxyguanine an abundant form of oxidative DNA damage, causes G- - - -T and A- - - -C substitutions, J. Biol. Chem. 267 (1992) 166–172. [48] M.T. Russo, M.F. Blasi, F. Chiera, P. Fortini, P. Degan, P. Macpherson, M. Furuichi, Y. Nakabeppu, P. Karran, G. Aquilina, M. Bignami, The oxidized deoxynucleoside triphosphate pool is a significant contributor to genetic

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92

[49]

[50] [51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72] [73]

instability in mismatch repair-deficient cells, Mol. Cell. Biol. 24 (2004) 465–474. E. Speina, K.D. Arczewska, D. Gackowski, M. Zielinska, A. Siomek, J. Kowalewski, R. Olinski, B. Tudek, J.T. Kusmierek, Contribution of hMTH1 to the maintenance of 8-oxoguanine levels in lung DNA of non-small-cell lung cancer patients, J. Natl. Cancer Inst. 97 (2005) 384–395. L.J. Marnett, Lipid peroxidation-DNA damage by malondialdehyde, Mutat. Res. 424 (1999) 83–95. A. Chenna, C.R. Iden, Characterization of 2 -deoxycytidine and 2 deoxyuridine adducts formed in reactions with acrolein and 2-bromoacrolein, Chem. Res. Toxicol. 6 (1993) 261–268. A. Chenna, R.A. Rieger, C.R. Iden, Characterization of thymidine adducts formed by acrolein and 2-bromoacrolein, Carcinogenesis 13 (1992) 2361–2365. A. Barbin, H. Bartsch, P. Leconte, M. Radman, Studies on the miscoding properties of 1,N6-ethenoadenine and 3,N4-ethenocytosine, DNA reaction products of vinyl chloride metabolites, during in vitro DNA synthesis, Nucleic Acids Res. 9 (1981) 375–387. P. Kowalczyk, J.M. Ciesla, M. Komisarski, J.T. Kusmierek, B. Tudek, Long-chain adducts of trans-4-hydroxy-2-nonenal to DNA bases cause recombination, base substitutions and frameshift mutations in M13 phage, Mutat. Res. 550 (2004) 33–48. L. Maddukuri, E. Speina, M. Christiansen, D. Dudzinska, J. Zaim, T. Obtulowicz, S. Kabaczyk, M. Komisarski, Z. Bukowy, J. Szczegielniak, A. Wojcik, J.T. Kusmierek, T. Stevnsner, V.A. Bohr, B. Tudek, Cockayne syndrome group B protein is engaged in processing of DNA adducts of lipid peroxidation product trans-4-hydroxy-2-nonenal, Mutat. Res. 666 (2009) 23–31. J. Nair, F. Gansauge, H. Beger, P. Dolara, G. Winde, H. Bartsch, Increased ethenoDNA adducts in affected tissues of patients suffering from Crohn’s disease, ulcerative colitis, and chronic pancreatitis, Antioxid. Redox Signal. 8 (2006) 1003–1010. P. Fortini, E. Dogliotti, Base damage and single-strand break repair: mechanisms and functional significance of short- and long-patch repair subpathways, DNA Repair (Amst.) 6 (2007) 398–409. K.H. Almeida, R.W. Sobol, A unified view of base excision repair: lesiondependent protein complexes regulated by post-translational modification, DNA Repair (Amst.) 6 (2007) 695–711. M.L. Hegde, T.K. Hazra, S. Mitra, Early steps in the DNA base excision/singlestrand interruption repair pathway in mammalian cells, Cell Res. 18 (2008) 27–47. A.B. Robertson, A. Klungland, T. Rognes, I. Leiros, DNA repair in mammalian cells: base excision repair: the long and short of it, Cell. Mol. Life Sci. 66 (2009) 981–993. C. Colussi, E. Parlanti, P. Degan, G. Aquilina, D. Barnes, P. Macpherson, P. Karran, M. Crescenzi, E. Dogliotti, M. Bignami, The mammalian mismatch repair pathway removes DNA 8-oxodGMP incorporated from the oxidized dNTP pool, Curr. Biol. 12 (2002) 912–918. H. Hayakawa, A. Taketomi, K. Sakumi, M. Kuwano, M. Sekiguchi, Generation and elimination of 8-oxo-7,8-dihydro-2 -deoxyguanosine 5 -triphosphate, a mutagenic substrate for DNA synthesis, in human cells, Biochemistry 34 (1995) 89–95. T. Tsuzuki, A. Egashira, H. Igarashi, T. Iwakuma, Y. Nakatsuru, Y. Tominaga, H. Kawate, K. Nakao, K. Nakamura, F. Ide, S. Kura, Y. Nakabeppu, M. Katsuki, T. Ishikawa, M. Sekiguchi, Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase, Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 11456–11461. K. Sakumi, Y. Tominaga, M. Furuichi, P. Xu, T. Tsuzuki, M. Sekiguchi, Y. Nakabeppu, Ogg1 knockout-associated lung tumorigenesis and its suppression by Mth1 gene disruption, Cancer Res. 63 (2003) 902–905. K. Sakamoto, Y. Tominaga, K. Yamauchi, Y. Nakatsu, K. Sakumi, K. Yoshiyama, A. Egashira, S. Kura, T. Yao, M. Tsuneyoshi, H. Maki, Y. Nakabeppu, T. Tsuzuki, MUTYH-null mice are susceptible to spontaneous and oxidative stress induced intestinal tumorigenesis, Cancer Res. 67 (2007) 6599–6604. Y. Xie, H. Yang, C. Cunanan, K. Okamoto, D. Shibata, J. Pan, D.E. Barnes, T. Lindahl, M. McIlhatton, R. Fishel, J.H. Miller, Deficiencies in mouse Myh and Ogg1 result in tumor predisposition and G to T mutations in codon 12 of the K-ras oncogene in lung tumors, Cancer Res. 64 (2004) 3096–3102. M.M. Slupska, W.M. Luther, J.H. Chiang, H. Yang, J.H. Miller, Functional expression of hMYH, a human homolog of the Escherichia coli MutY protein, J. Bacteriol. 181 (1999) 6210–6213. G. Dianov, C. Bischoff, J. Piotrowski, V.A. Bohr, Repair pathways for processing of 8-oxoguanine in DNA by mammalian cell extracts, J. Biol. Chem. 273 (1998) 33811–33816. J.P. Radicella, C. Dherin, C. Desmaze, M.S. Fox, S. Boiteux, Cloning and characterization of hOGG1, a human homolog of the OGG1 gene of Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. U.S.A. 94 (1997) 8010–8015. K. Shinmura, J. Yokota, The OGG1 gene encodes a repair enzyme for oxidatively damaged DNA and is involved in human carcinogenesis, Antioxid. Redox Signal. 3 (2001) 597–609. N.A. Kuznetsov, V.V. Koval, D.O. Zharkov, G.A. Nevinsky, K.T. Douglas, O.S. Fedorova, Kinetics of substrate recognition and cleavage by human 8oxoguanine-DNA glycosylase, Nucleic Acids Res. 33 (2005) 3919–3931. S. Bjelland, E. Seeberg, Mutagenicity, toxicity and repair of DNA base damage induced by oxidation, Mutat. Res. 531 (2003) 37–80. N. Al-Tassan, N.H. Chmiel, J. Maynard, N. Fleming, A.L. Livingston, G.T. Williams, A.K. Hodges, D.R. Davies, S.S. David, J.R. Sampson, J.P. Cheadle,

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88] [89] [90]

[91]

[92] [93]

[94]

[95]

[96]

[97] [98]

91

Inherited variants of MYH associated with somatic G:C → T:A mutations in colorectal tumors, Nat. Genet. 30 (2002) 227–232. V.S. Sidorenko, A.P. Grollman, P. Jaruga, M. Dizdaroglu, D.O. Zharkov, Substrate specificity and excision kinetics of natural polymorphic variants and phosphomimetic mutants of human 8-oxoguanine-DNA glycosylase, FEBS J. 276 (2009) 5149–5162. J.W. Hill, M.K. Evans, Dimerization and opposite base-dependent catalytic impairment of polymorphic S326C OGG1 glycosylase, Nucleic Acids Res. 34 (2006) 1620–1632. C. Dherin, J.P. Radicella, M. Dizdaroglu, S. Boiteux, Excision of oxidatively damaged DNA bases by the human alpha-hOgg1 protein and the polymorphic alpha-hOgg1(Ser326Cys) protein which is frequently found in human populations, Nucleic Acids Res. 27 (1999) 4001–4007. M. Goodman, R.M. Bostick, C. Dash, P. Terry, W.D. Flanders, J. Mandel, A summary measure of pro- and anti-oxidant exposures and risk of incident sporadic, colorectal adenomas, Cancer Causes Control 19 (2008) 1051–1064. L. Chen, A. Elahi, J. Pow-Sang, P.J. Lazarus, Park Association between polymorphism of human oxoguanine glycosylase 1 and risk of prostate cancer, J. Urol. 170 (2003) 2471–2474. E.Y. Cho, A. Hildesheim, C.J. Chen, M.M. Hsu, I.H. Chen, B.F. Mittl, P.H. Levine, M.Y. Liu, J.Y. Chen, L.A. Brinton, Y.J. Cheng, C.S. Yang, Nasopharyngeal carcinoma and genetic polymorphisms of DNA repair enzymes XRCC1 and hOGG1, Cancer Epidemiol. Biomarkers Prev. 12 (2003) 1100–1104. R. Hansen, M. Saebo, C.F. Skjelbred, B.A. Nexo, P.C. Hagen, G. Bock, I.M. Bowitz Lothe, E. Johnson, S. Aase, I.L. Hansteen, U. Vogel, E.H. Kure, GPX Pro198Leu and OGG1 Ser326Cys polymorphisms and risk of development of colorectal adenomas and colorectal cancer, Cancer Lett. 229 (2005) 85–91. T. Sliwinski, R. Krupa, M. Wisniewska-Jarosinska, E. Pawlowska, J. Lech, J. Chojnacki, J. Blasiak, Common polymorphisms in the XPD and hOGG1 genes are not associated with the risk of colorectal cancer in a Polish population, Tohoku J. Exp. Med. 218 (2009) 185–191. T. Paz-Elizur, M. Krupsky, S. Blumenstein, D. Elinger, E. Schechtman, Z. Livneh, DNA repair activity for oxidative damage and risk of lung cancer, J. Natl. Cancer Inst. 95 (2003) 1312–1319. J. Janik, M. Swoboda, B. Janowska, J.M. Ciesla, D. Gackowski, J. Kowalewski, R. Olinski, B. Tudek, E. Speina, 8-Oxoguanine incision activity is impaired in lung tissues of NSCLC patients with the polymorphism of OGG1 and XRCC1 genes, Mutat. Res. 709–710 (2011) 21–31. T. Paz-Elizur, R. Ben-Yosef, D. Elinger, A. Vexler, M. Krupsky, A. Berrebi, A. Shani, E. Schechtman, L. Freedman, Z. Livneh, Reduced repair of the oxidative 8-oxoguanine DNA damage and risk of head and neck cancer, Cancer Res. 66 (2006) 11683–11689. M. Saparbaev, K. Kleibl, J. Laval, Escherichia coli, Saccharomyces cerevisiae, rat and human 3-methyladenine DNA glycosylases repair 1,N6-ethenoadenine when present in DNA, Nucleic Acids Res. 23 (1995) 3750–3755. M. Saparbaev, J. Laval, 3,N4-ethenocytosine, a highly mutagenic adduct, is a primary substrate for Escherichia coli double-stranded uracil-DNA glycosylase and human mismatch-specific thymine-DNA glycosylase, Proc. Natl. Acad. Sci. U.S.A. 95 (1998) 8508–8513. B. Kavli, O. Sundheim, M. Akbari, M. Otterlei, H. Nilsen, F. Skorpen, P.A. Aas, L. Hagen, H.E. Krokan, G. Slupphaug, hUNG2 is the major repair enzyme for removal of uracil from U:A matches, U:G mismatches, and U in singlestranded DNA, with hSMUG1 as a broad specificity backup, J. Biol. Chem. 277 (2002) 39926–39936. A. Bellacosa, Role of MED1 (MBD4) Gene in DNA repair and human cancer, J. Cell. Physiol. 187 (2001) 137–144. J. Jiricny, M. Menigatti, DNA cytosine demethylation: are we getting close? Cell 135 (2008) 1167–1169. M. Saparbaev, S. Langouet, C.V. Privezentzev, F.P. Guengerich, H. Cai, R.H. Elder, J. Laval, 1,N(2)-ethenoguanine, a mutagenic DNA adduct, is a primary substrate of Escherichia coli mismatch-specific uracil-DNA glycosylase and human alkylpurine-DNA-N-glycosylase, J. Biol. Chem. 277 (2002) 26987–26993. C.V. Privezentzev, M. Saparbaev, J. Laval, The HAP1 protein stimulates the turnover of human mismatch-specific thymine-DNA-glycosylase to process 3,N(4)-ethenocytosine residues, Mutat. Res. 480–481 (2001) 277–284. B. Demple, J.S. Sung, Molecular and biological roles of Ape1 protein in mammalian base excision repair, DNA Repair (Amst.) 4 (2005) 1442–1449. S. Um, M. Harbers, A. Benecke, B. Pierrat, R. Losson, P. Chambon, Retinoic acid receptors interact physically and functionally with the T:G mismatch-specific thymine-DNA glycosylase, J. Biol. Chem. 273 (1998) 20728–20736. M. Tini, A. Benecke, S.J. Um, J. Torchia, R.M. Evans, P. Chambon, Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription, Mol. Cell 9 (2002) 265–277. C. Missero, M.T. Pirro, S. Simeone, M. Pischetola, R. Di Lauro, The DNA glycosylase T:G mismatch-specific thymine DNA glycosylase represses thyroid transcription factor-1-activated transcription, J. Biol. Chem. 276 (2001) 33569–33575. L. Gros, A.V. Maksimenko, C.V. Privezentzev, J. Laval, M.K. Saparbaev, Hijacking of the human alkyl-N-purine-DNA glycosylase by 3,N4-ethenocytosine, a lipid peroxidation-induced DNA adduct, J. Biol. Chem. 279 (2004) 17723–17730. B. Tudek, Base excision repair modulation as a risk factor for human cancers, Mol. Aspects Med. 28 (2007) 258–275. V. Winnepenninckx, V. Lazar, S. Michiels, P. Dessen, M. Stas, S.R. Alonso, M.F. Avril, P.L. Ortiz Romero, T. Robert, O. Balacescu, A.M. Eggermont, G. Lenoir, A. Sarasin, T. Tursz, J.J. van den Oord, A. Spatz, Gene expression profiling of

92

[99]

[100]

[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

[109] [110]

[111]

[112]

[113]

[114] [115]

B. Tudek, E. Speina / Mutation Research 736 (2012) 82–92 primary cutaneous melanoma and clinical outcome, J. Natl. Cancer Inst. 98 (2006) 472–482. K. Janssen, K. Schlink, W. Gotte, B. Hippler, B. Kaina, F. Oesch, DNA repair activity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes is not dependent on genetic polymorphism Ser326/Cys326, Mutat. Res. 486 (2001) 207–216. A. Jensen, M. Lohr, L. Eriksen, M. Gronbaek, E. Dorry, S. Loft, P. Moller, Influence of the OGG1 Ser326Cys polymorphism on oxidatively damaged DNA and repair activity, Free Radic. Biol. Med. 52 (2012) 118–125. D.J. Smart, J.K. Chipman, N.J. Hodges, Activity of OGG1 variants in the repair of pro-oxidant-induced 8-oxo-2 -deoxyguanosine, DNA Repair (Amst.) 5 (2006) 1337–1345. A. Bravard, M. Vacher, E. Moritz, L. Vaslin, J. Hall, B. Epe, J.P. Radicella, Oxidation status of human OGG1-S326C polymorphic variant determines cellular DNA repair capacity, Cancer Res. 69 (2009) 3642–3649. M.S. Cooke, M.D. Evans, R. Dove, R. Rozalski, D. Gackowski, A. Siomek, J. Lunec, R. Olinski, DNA repair is responsible for the presence of oxidatively damaged DNA lesions in urine, Mutat. Res. 574 (2005) 58–66. S. Loft, P. Danielsen, M. Lohr, K. Jantzen, J.G. Hemmingsen, M. Roursgaard, D.G. Karotki, P. Moller, Urinary excretion of 8-oxo-7,8-dihydroguanine as biomarker of oxidative damage to DNA, Arch. Biochem. Biophys. 518 (2012) 142–150. T. Obtulowicz, A. Winczura, E. Speina, M. Swoboda, J. Janik, B. Janowska, J.M. Ciesla, P. Kowalczyk, A. Jawien, D. Gackowski, Z. Banaszkiewicz, I. Krasnodebski, A. Chaber, R. Olinski, J. Nair, H. Bartsch, T. Douki, J. Cadet, B. Tudek, Aberrant repair of etheno-DNA adducts in leukocytes and colon tissue of colon cancer patients, Free Radic. Biol. Med. 49 (2010) 1064–1071. M. Graziewicz, D.A. Wink, F. Laval, Nitric oxide inhibits DNA ligase activity: potential mechanisms for NO-mediated DNA damage, Carcinogenesis 17 (1996) 2501–2505. D.A. Wink, J. Laval, The Fpg protein a DNA repair enzyme, is inhibited by the biomediator nitric oxide in vitro and in vivo, Carcinogenesis 15 (1994) 2125–2129. M. Jaiswal, N.F. LaRusso, N. Nishioka, Y. Nakabeppu, G.J. Gores, Human Ogg1 a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide, Cancer Res. 61 (2001) 6388–6393. M.A. Graziewicz, B.J. Day, W.C. Copeland, The mitochondrial DNA polymerase as a target of oxidative damage, Nucleic Acids Res. 30 (2002) 2817–2824. Z. Feng, W. Hu, M.S. Tang, Trans-4-hydroxy-2-nonenal inhibits nucleotide excision repair in human cells: a possible mechanism for lipid peroxidation-induced carcinogenesis, Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 8598–8602. H. Bartsch, J. Nair, Accumulation of lipid peroxidation-derived DNA lesions: potential lead markers for chemoprevention of inflammation-driven malignancies, Mutat. Res. 591 (2005) 34–44. S.H. Cherng, K.H. Huang, S.C. Yang, T.C. Wu, J.L. Yang, H. Lee, Human 8oxoguanine DNA glycosylase 1 mRNA expression as an oxidative stress exposure biomarker of cooking oil fumes, J. Toxicol. Environ. Health A 65 (2002) 265–278. A. Das, T.K. Hazra, I. Boldogh, S. Mitra, K.K. Bhakat, Induction of the human oxidized base-specific DNA glycosylase NEIL1 by reactive oxygen species, J. Biol. Chem. 280 (2005) 35272–35280. B. Hang, Repair of exocyclic DNA adducts: rings of complexity, Bioessays 26 (2004) 1195–1208. J. Ringvoll, M.N. Moen, L.M. Nordstrand, L.B. Meira, B. Pang, A. Bekkelund, P.C. Dedon, S. Bjelland, L.D. Samson, P.O. Falnes, A. Klungland, AlkB homologue 2-mediated repair of ethenoadenine lesions in mammalian DNA, Cancer Res. 68 (2008) 4142–4149.

[116] K. Schmid, J. Nair, G. Winde, I. Velic, H. Bartsch, Increased levels of promutagenic etheno-DNA adducts in colonic polyps of FAP patients, Int. J. Cancer 87 (2000) 1–4. [117] M. Luchtenborg, M.P. Weijenberg, P.A. Wark, A.M. Saritas, G.M. Roemen, G.N. van Muijen, A.P. de Bruine, P.A. van den Brandt, A.F. de, Goeij mutations in APC CTNNB1 and K-ras genes and expression of hMLH1 in sporadic colorectal carcinomas from the Netherlands Cohort Study, BMC Cancer 5 (2005) 160. [118] A.S. Jaiswal, R. Balusu, M.L. Armas, C.N. Kundu, S. Narayan, Mechanism of adenomatous polyposis coli (APC)-mediated blockage of long-patch base excision repair, Biochemistry 45 (2006) 15903–15914. [119] S. Narayan, A.S. Jaiswal, R. Balusu, Tumor suppressor APC blocks DNA polymerase beta-dependent strand displacement synthesis during long patch but not short patch base excision repair and increases sensitivity to methylmethane sulfonate, J. Biol. Chem. 280 (2005) 6942–6949. [120] D. Cortazar, C. Kunz, Y. Saito, R. Steinacher, P. Schar, The enigmatic thymine DNA glycosylase, DNA Repair (Amst.) 6 (2007) 489–504. [121] A.S. Jaiswal, S. Narayan, Assembly of the base excision repair complex on abasic DNA and role of adenomatous polyposis coli on its functional activity, Biochemistry 50 (2011) 1901–1909. [122] A. Zaky, C. Busso, T. Izumi, R. Chattopadhyay, A. Bassiouny, S. Mitra, K.K. Bhakat, Regulation of the human AP-endonuclease (APE1/Ref-1) expression by the tumor suppressor p53 in response to DNA damage, Nucleic Acids Res. 36 (2008) 1555–1566. [123] C.S. Busso, T. Iwakuma, T. Izumi, Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway, Oncogene 28 (2009) 1616–1625. [124] J. Nair, F. Gansauge, H. Beger, P. Dolara, G. Winde, H. Bartsch, Increased ethenoDNA adducts in affected tissues of patients suffering from Crohn’s disease ulcerative colitis, and chronic pancreatitis, Antioxid. Redox Signal. 8 (2006) 1003–1010. [125] L.J. Hofseth, The adaptive imbalance to genotoxic stress: genome guardians rear their ugly heads, Carcinogenesis 25 (2004) 1787–1793. [126] V. Singh-Gupta, H. Zhang, S. Banerjee, D. Kong, J.J. Raffoul, F.H. Sarkar, G.G. Hillman, Radiation-induced HIF-1alpha cell survival pathway is inhibited by soy isoflavones in prostate cancer cells, Int. J. Cancer 124 (2009) 1675–1684. [127] J.W. Hill, T.K. Hazra, T. Izumi, S. Mitra, Stimulation of human 8-oxoguanineDNA glycosylase by AP-endonuclease: potential coordination of the initial steps in base excision repair, Nucleic Acids Res. 29 (2001) 430–438. [128] S. Cortellino, J. Xu, M. Sannai, R. Moore, E. Caretti, A. Cigliano, M. Le Coz, K. Devarajan, A. Wessels, D. Soprano, L.K. Abramowitz, M.S. Bartolomei, F. Rambow, M.R. Bassi, T. Bruno, M. Fanciulli, C. Renner, A.J. Klein-Szanto, Y. Matsumoto, D. Kobi, I. Davidson, C. Alberti, L. Larue, A. Bellacosa, Thymine DNA glycosylase is essential for active DNA demethylation by linked deaminationbase excision repair, Cell 146 (2011) 67–79. [129] C. Kunz, F. Focke, Y. Saito, D. Schuermann, T. Lettieri, J. Selfridge, P. Schar, Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil, PLoS Biol. 7 (2009) e91. [130] S. Amente, L. Lania, E.V. Avvedimento, B. Majello, DNA oxidation drives Myc mediated transcription, Cell Cycle 9 (2010) 3002–3004. [131] S. Amente, A. Bertoni, A. Morano, L. Lania, E.V. Avvedimento, B. Majello, LSD1-mediated demethylation of histone H3 lysine 4 triggers Myc-induced transcription, Oncogene 29 (2010) 3691–3702. [132] T. Sexton, F. Bantignies, G. Cavalli, Genomic interactions: chromatin loops and gene meeting points in transcriptional regulation, Semin. Cell Dev. Biol. 20 (2009) 849–855. [133] B. Perillo, M.N. Ombra, A. Bertoni, C. Cuozzo, S. Sacchetti, A. Sasso, L. Chiariotti, A. Malorni, C. Abbondanza, E.V. Avvedimento, DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression, Science 319 (2008) 202–206.