Lipid peroxidation in face of DNA damage, DNA repair and other cellular processes

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Lipid peroxidation in face of DNA damage, DNA repair and other cellular processes ⁎

Barbara Tudeka,b, , Daria Zdżalik-Bieleckac, Agnieszka Tudekd, Konrad Kosickib, Anna Fabisiewicze, Elżbieta Speinaa a

Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland c Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Ksiecia Trojdena 4, 02-109 Warsaw, Poland d Department of Molecular Biology and Genetics, Aarhus University, C. F. Mollers Alle 3, 8000 Aarhus, Denmark e Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, Warsaw 02-781, Poland b

A R T I C L E I N F O

A B S T R A C T

Keywords: Etheno-DNA adducts Propano-DNA adducts BER NER NIR AlkB Homologous recombination Lipid peroxidation Enzyme modification RNA processing

Exocyclic adducts to DNA bases are formed as a consequence of exposure to certain environmental carcinogens as well as inflammation and lipid peroxidation (LPO). Complex family of LPO products gives rise to a variety of DNA adducts, which can be grouped in two classes: (i) small etheno-type adducts of strong mutagenic potential, and (ii) bulky, propano-type adducts, which block replication and transcription, and are lethal lesions. EthenoDNA adducts are removed from the DNA by base excision repair (BER), AlkB and nucleotide incision repair enzymes (NIR), while substituted propano-type lesions by nucleotide excision repair (NER) and homologous recombination (HR). Changes of the level and activity of several enzymes removing exocyclic adducts from the DNA was reported during carcinogenesis. Also several beyond repair functions of these enzymes, which participate in regulation of cell proliferation and growth, as well as RNA processing was recently described. In addition, adducts of LPO products to proteins was reported during aging and age-related diseases. The paper summarizes pathways for exocyclic adducts removal and describes how proteins involved in repair of these adducts can modify pathological states of the organism.

1. Formation of exocyclic DNA adducts from exogenous and endogenous sources Exocyclic DNA adducts are among the most deleterious DNA lesions. Plethora of structures were described in the literature, depending on initiating events. Environmental carcinogens, like vinyl chloride (VC), its metabolite chloroacetaldehyde (CAA) or chloroethylene oxide induce etheno-type adducts, which are characterized by five-membered exocyclic ring between nitrogen atoms situated in the purine or pyrimidine ring and exocyclic nitrogen of DNA base amino- group [1– 3]. Etheno-DNA adducts were also identified in animals and humans not exposed to carcinogens, which suggests their endogenous formation [4,5]. Although it is widely believed that formation of exocyclic adducts is caused by inflammation-induced lipid peroxidation products, direct mechanism is not clear. LPO results in the formation of plethora of compounds, which can be classified into few groups: aldehydes (e.g.

acrolein, (ACR), malondialdehyde (MDA)), alkenals (e.g. hex-2-enal, oct-2-enal), hydroxyalkenals (e.g. 4-hydroxy-2-nonenal (HNE), and other groups, like alkanals, alkadienals, ketones, osazones. These products trigger formation of distinct groups of linear and cyclic LPO DNA adducts. They can be divided into propano- and etheno-type adducts either unsubstituted or substituted with side chains of different length, depending on the structure of reacting LPO product (Fig. 1). The best described compound, malondialdehyde reacts with DNA at guanine, adenine and cytosine to form cyclic 3-(2-deoxy-beta-D-erythropentofuranosyl)pyrimido-[1,2α]purine-10(3H)-one (M1dG) adduct and linear N6-(3-oxopropenyl)−2′-deoxyadenosine (M1dA) and N4-(3-oxopropenyl)−2′-deoxycytosine (M1dC) adducts, respectively [6]. M1dG (Fig. 1) is the major MDA-DNA adduct and was detected in untreated human and rodent tissues [7–9]. Exocyclic propano-type DNA adducts are formed by the attachment of LPO product that generates additional saturated, six-member ring in

Abbreviations: εAde, 1,N6-ethenoadenine; εCyt, 3,N4-ethenocytosine; 1, N2- εGua, 1,N2-ethenoguanine; BER, base excision repair; NER, nucleotide excision repair; NIR, nucleotide incision repair; HR, homologous recombination; NHEJ, non-homologous end joining; LPO, lipid peroxidation ⁎ Corresponding author at: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland. E-mail address: [email protected] (B. Tudek). http://dx.doi.org/10.1016/j.freeradbiomed.2016.11.043 Received 8 September 2016; Received in revised form 20 November 2016; Accepted 27 November 2016 0891-5849/ © 2016 Elsevier Inc. All rights reserved.

Please cite this article as: Tudek, B., Free Radical Biology and Medicine (2016), http://dx.doi.org/10.1016/j.freeradbiomed.2016.11.043

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ETHENO-ADDUCTS

Repair pathways:

N

LPO products, 4-hydroxy-2-nonenal [14,18]. Under oxidizing conditions HNE may form small amounts of unsubstituted etheno-DNA adducts, however the available data from in vitro studies are not consistent. Chen and Chung [14] demonstrated that under oxidizing conditions the ratio of unsubstituted to substituted ethenoadenine is 6:100, of unsubstituted to substituted ethenoguanine equals 24:100, and the number of unsubstituted ethenoadducts is significantly decreased under nitrogen. However, our previous in vitro studies showed that under oxidizing conditions only 2’-deoxyguanosine yielded unsubstituted 1,N2-εdG, and only in the amount of 1–2% of modified dG [12]. Unsubstituted ethenoadducts are formed from unsaturated fatty acids in animals and humans [18], however the exact pathway of their formation is not clear. One suggested possibility of 1,N2-εdG formation is from HNE precursor, 4-hydroperoxy-2-nonenal (HPNE) [19,20]. Some exocyclic DNA adducts are chemically unstable and spontaneously rearrange into secondary lesions differing in structure, interactions with DNA polymerases, coding properties and repair enzymes. 1,N6-Ethenoadenine, 1,N2-ethenoguanine, pyrimido[1,2-α]purin10(3 H)-one, and γ-OH-1,N2-propanoguanine undergo hydrolytic ring opening to form ring-opened adducts. 1,N2-Ethenoguanine rearranges into N1-(2-oxoethyl)Gua [21]. M1dG, when placed opposite cytosine in duplex DNA, spontaneously converts to the ring-opened derivative N2(3-oxo-1-propenyl)-dG [22]. Similar ring opening was observed for γOH-1,N2-propanodG to form a structure that facilitates pairing with dC during DNA replication and accounts for the lack of mutagenicity of this DNA adduct [23]. Tsou et al. [24] and Basu et al. [25,26] have shown that 1,N6-ethenoadenine is rearranged into a pyrimidine ring-opened derivative, 4-amino-5-(imidazol-2-yl)imidazole, which has about 20fold higher mutagenic potency in E. coli than the parental εAde, and causes different types of mutations [26]. Our subsequent studies have shown that at pH 7.0, the stability of N-glycosidic bond in εdA is about 20-fold lower than that in dA, and that εdA either depurinates or converts into three products: εdA→B→C→D [27] (Fig. 2). The extent of this rearrangement is rather low. In vitro studies have shown that in single-stranded oligodeoxynucleotide at neutrality 2–3% of εdA per week undergoes spontaneous rearrangement [27]; unfortunately there are no data on the rate of rearrangement in dsDNA and in the cells. However, the rearrangement with the production of AP sites and subsequent DNA breaks may be partially responsible for the induction of chromosomal aberrations and sister chromatid exchanges by vinyl chloride and LPO compounds [1].

N N

N N

N O

N

N

dA

dC O

O N

N N

N H

BER AlkB NIR

dR

dR

N

N

N

N

N

N

dR

dR

1,N2-

N2,3-

dG

dG

BULKY EXOCYCLIC ADDUCTS O N N H

OH N

N

O N

N H3C

N dR

OH

M1dG

N H

N

N dR

NER HR NHEJ

HNE dG propano-type O

OH

N

N

H3C OH

N H

N

N dR

HNE dG etheno-type Fig. 1. Examples of diverse structures of exocyclic DNA adducts and pathways engaged in their repair. εdA, ethenodeoxyguanosine; εdC, ethenodeoxycytidine; 1,N2-εdG, 1,N2ethenodeoxyguanosine; N2,3-εdG, N2,3-ethenodeoxyguanosine; M1dG, 3-(2-deoxy-beta-Derythro-pentofuranosyl)pyrimido-[1,2α]purine-10(3H)-one; HNE, 4-hydroxy-2-nonenal.

a DNA base. These adducts are derived from the reaction of DNA with acrolein, crotonaldehyde or HNE and other compounds. Acr-dG, Cro-dG and HNE-dG were found in rodent and human tissues [10,11], however all DNA bases can probably be a target for LPO products addition. For example, in vitro HNE may directly react with guanosine, adenosine, cytidine and thymidine moiety in the DNA. Thymidine was shown to be modified with about two orders of magnitude lower efficiency than other DNA bases [12]. The reaction of LPO products with DNA bases involves Michael addition, followed by Schiff base formation by aldehyde group, and all this results in creation of 1N2- propano-2′deoxyguanosine (PdG) (Fig. 1) as well as plethora of adducts to Cyt, Ade and Thy. Thymine adducts are linear, due to the fact that thymine is deprived of exocyclic amino group. HNE and other LPO adducts to Gua, Cyt and Ade are cyclic in nucleosides, nucleotides and singlestranded DNA. In double stranded DNA the reaction of aldehyde group is reversible. This results in the appearance of linear adducts, which may form new Schiff base linkage with the amino- groups of nucleic acids and amino acids to create inter- and intra-strand DNA-DNA crosslinks and DNA-protein crosslinks. In the presence of oxygen alkenals, like HNE undergo epoxidation and react with dG, dC or dA moieties in the DNA that lead to formation of ethenoadducts substituted with side chains (for HNE heptyl side chain) [13,14] (Fig. 1). The complexity of adducts to DNA bases is increased by the existence of stereoisomers [15,16]. HNE stereoisomers were shown to have different mutagenic potential [17]. Formation of unsubstituted etheno-DNA adducts from LPO products is controversial. It is suggested that they derive from one of the major

Excised by:

ANPG

Fpg, Nth

Formation of AP-site Fig. 2. Spontaneous rearrangement of 1,N6-ethenoadenine; resulting modifications and their excision by DNA glycosylases. Rearrangement occurs slowly in pH 7.00 but is significantly accelerated in alkaline conditions. ANPG, alkyladenine DNA N-glycosylase; Fpg, formamidopyrimidine DNA N-glycosylase; Nth, thymine glycol DNA N-glycosylase (Endonuclease III).

2

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3.1. Base excision repair

Table 1 The types of base changes induced by selected DNA adducts observed in vitro, in E. coli, and in mammalian cells. DNA Adducta

εdA

4-Amino-5-imidazol2-yl)imidazole (compound C) εdC

εdC·H2O 1,N2-εdG

N2,3εdG HO-ethanodG

M1dG PdG γ-OH-PdG

Base excision repair (BER) is considered to be the main removal pathway of non bulky DNA alterations arising from oxidation, alkylation and spontaneous hydrolysis [34]. The BER process usually involves the excision of a single damaged nucleotide (BER small patch), but there is a second pathway (BER long patch), involving 2–10 nucleotides [35,36]. Typically, the repair involves multiple enzymes such as DNA N-glycosylase (or DNA N-glycosylase/AP lyase), AP endonuclease, DNA polymerase(s), and DNA ligase (Fig. 3). This is initiated by DNA Nglycosylase that recognizes and removes the damaged base or a normal base from mismatch by hydrolyzing the N-glycosidic bond [37–39]. The best substrates for bacterial and yeast mismatch specific uracil DNA Nglycosylase (Mug) were found to be DNA containing lipid peroxidation products of cytosine and guanine, 3,N4-ethenocytosine, 8-(hydroxymethyl)-3,N4-ethenocytosine (8-HM-εCyt), and 1,N2-ethenoguanine. Mug is about 5-fold more active in the excision of 3,N4-εCyt and 8HM-εC from 3,N4-εCyt:Gua and 8-HM-εCyt:Gua mispairs, and 2.5-fold more active in the excision of 1,N2-εGua from 1,N2-εGua:Cyt mispairs, than of uracil from Ura:Gua mismatch [40–42]. Mug functional homolog in human cells, thymine DNA N-glycosylase (TDG), is also a 3,N4-εCyt glycosylase, but it does not repair 1,N2-εGua. For TDG, ethenocytosine mispaired with guanine is almost as good substrate as Ura:Gua mismatch [40,43]. Mug and TDG excise εC paired with any of the natural bases with comparable efficiency; however, the best substrate for both enzymes is εCyt paired with G. Mug glycosylase activity against 1,N2-εGua is dependent on the opposite base and decreases in the following order: εGua:Cyt > Gua≥Ade > Thy. The other uracil DNA glycosylases, mammalian methyl-CpG binding domain protein MBD4 (or MED1) and eukaryotic single-stranded monofunctional uracil DNA glycosylase (SMUG1) were reported to have a weak εCyt-glycosylase activity releasing εCyt from εCyt:Gua pairs [44,45]. Repair glycosylases specific towards the alkylation DNA damage, E. coli alkyladenine DNA N-glycosylase, AlkA, and its functional homologs, S. cerevisiae Mag and human ANPG (also called MPG or AAG), are monofunctional DNA N-glycosylases that catalyze the removal of structurally diverse groups of modified bases. ANPG efficiently removes also deaminated derivatives of adenine, hypoxanthine [46,47], and a base alkylated via lipid peroxidation, such as εAde. Another LPO derivative, 1,N2-ethenoguanine, is also released by ANPG, although with low efficiency [41]. ANPG preferentially repairs 1,N2-ethenoguanine when paired with Cyt, followed by Thy and Ade, but the enzyme does not repair 1,N2-εGua mispaired with Gua [41]. Although AlkA and Mag proteins have been shown to release also hypoxanthine and εAde, but not 1,N2-εGua, from the DNA in vitro [46,48], the efficiency of this process is extremely low, indicating that the repair of hypoxanthine and εA probably does not occur in vivo either in bacteria or in yeast. Contrary to ANPG and Mag, AlkA repairs also N2,3-εGua, but with moderate efficiency [49]. The genotoxic effect and repair mechanism of εAde have been extensively studied and fairly well documented in literature. Our studies clarified the fate of εAde in DNA and repair of the derivatives resulting from its chemical rearrangements [27]. We have found that 1,N6-ethenoadenine derivatives were not eliminated from the DNA by human alkylpurine DNA N-glycosylase, which participates in the repair of parental εAde. One of these derivatives, compound B, was excised from the DNA by Fpg and Nth glycosylases, two BER E. coli enzymes that excise oxidized bases [27]. We also elucidated the fate of its rearrangement products (Fig. 2) during in vitro DNA synthesis. Product B constituted a much stronger replication block to in vitro DNA synthesis than the parental lesion and that nucleotide insertion opposite C was the easiest one for prokaryotic and eukaryotic DNA polymerases [50].

Mutagenic properties In vitro

E.coli

Mammalian cells

A→G, A→T > A→C [162] A→T > A→C

A→G > A→C, A→T [26,163] A→G, A→C, A→T [26] C→A, C→T

A→G > A→T

[166,167] C→T [169,170] GC→A, G→C, GC→TA [28] G→A [29] G→T, G→C, G→A [28] G→A, G→T [93] G→T [167] G→T [179]

[167] Not determined

[50] C→A, C→T > C→G [165] No incorporation [168] G→A, G→C [171] G→A [172,173] G→T, G→C [171] G→C [175] No incorporation [177] G→A, G→G [179]

[163,164] Not determined

C→A, C→T

G→A > G→T [21] G→T, G→A [174] Not determined

G→A, G→T [176] G→T, G→A [167,178] G→T, G→A [180]

a εdA, ethenodeoxyguanosine; εdC, ethenodeoxycytidine; 1,N2-εdG, 1,N2-ethenodeoxyguanosine; N2,3-εdG, N2,3-ethenodeoxyguanosine; M1dG, 3-(2-deoxy-beta-D-erythropentofuranosyl)pyrimido-[1,2α]purine-10(3H)-one; PdG, 1,N2- propano-2′-deoxyguanosine.

2. Biological properties of exocyclic DNA adducts The presence of unsubstituted etheno-adducted DNA bases in the template slightly inhibits DNA synthesis by replicative and damagespecific DNA polymerases, while substituted etheno-type and propanotype cyclic adducts constitute a strong barrier for replication [28,29]. The lesions with strong mutagenic potential are εAde, εCyt and 1,N2-εGua, particularly in mammalian cells, and much less in bacteria. Mutagenic properties of major exocyclic DNA adducts are summarized in Table 1. In mammals, ε-DNA adducts, additionally trigger chromosomal aberrations and recombination [1], as well as strand breaks due to the fact that beyond other reasons εAde strongly stimulates the activity of topoisomerase II [30]. Substituted LPO-derived cyclic DNA adducts, like HNE-DNA adducts strongly inhibit DNA synthesis by prokaryotic and eukaryotic DNA polymerases both in vitro and in cellular models [12]. In bypass of HNEDNA adducts cooperation of low-fidelity DNA polymerases was observed (see Section 4.3). It is also of interest that exocyclic bulky adducts, like HNE adducts strongly inhibit RNA synthesis both by prokaryotic and human RNA polymerases [31].

3. Repair of exocyclic DNA adducts Depending on the size of exocyclic DNA adducts different repair pathways are engaged in removal of these lesions from the DNA. Small, etheno-type DNA adducts are repaired by: (i) base excision repair (BER); (ii) nucleotide incision repair (NIR) and (iii) AlkB proteins, while bulky substituted propano- and substituted etheno-type adducts by nucleotide excision repair (NER) and homologous recombination (HR) [12,32,33] (Fig. 1). 3

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BER

5’

3’

NIR

5’ 3’

APE1 (NIR 1)

DNA glycosylase 5’ 3’

3’

5’

3’

5’

3’

5’

APE 3’

5’

5’

3’

PARP 5’

3’OH

5’P

3’

3’

5’

Pol

LONG PATCH

SHORT PATCH

5’ 5’

3’OH

5’P

3’

3’

Pol / PCNA

Ligase III XRCC1

3’

3’

3’

5’

5’

3’OH 5’P

5’ 3’

3’

5’

FEN1 PCNA 5’

5’

(NIR2) 3’OH

5’

3’OH

3’

Damaged base

ligase I (NIR4) PCNA

Inserted nucleotide

3’

(NIR3) 3’ 5’

5’

3’

3’

5’

Fig. 3. Base excision repair and nucleotide incision repair.

Thus, DNA glycosylase-independent removal of DNA base lesions might take place before BER, and act as a backup pathway to BER to remove ethenobases, thymine glycols and uracil residues present in genomic DNA in vivo.

3.2. Nucleotide incision repair An alternative BER pathway in which ε-DNA adducts can be repaired in DNA glycosylase-independent manner is nucleotide incision repair. In this pathway, the apurinic/apyrimidinic (AP) endonuclease incises DNA duplex 5′ to a damaged base and creates 5’-dangling damaged nucleotide and 3’-hydroxyl group that can be directly extended by DNA polymerase (Fig. 3, NIR1). Human major AP endonuclease, APE1, in addition to several oxidized bases [51,52] and uracil [53] incises DNA 5’ to εAde and εCyt [54]. The apparent kinetic parameters of the reactions suggest that APE1 has a high affinity for DNA containing εAde and εCyt residues but cleaves DNA duplexes at an extremely slow rate. The efficiency of APE1 damage-specific cleavage activity depends strongly on sequence context. The next step in damage processing in NIR pathway is elongation of free 3’OH group by DNA polymerase (Fig. 3, NIR2) and formation of a flap, which is then cut off by FEN1 endonuclease (Fig. 3, NIR3). The pathway is finished by DNA ligase, which seals broken DNA ends (Fig. 3, NIR4). In fact NIR stages 2–4 are the same as BER long patch pathway, and BER from NIR differs only by recognition/excision mechanism (Fig. 3), which requires DNA glycosylase in BER, but not in NIR. Interestingly, in certain archaeal organisms uracil residues are eliminated by apurinic/apyrimidinic (AP) endonucleases in the alternative NIR pathway. Mth212 protein from Methanothermobacter thermautotrophicus, which is homologous to human APE1 and E. coli APendonuclease, Xth shares DNA substrate specificity with human APE1.

3.3. AlkB mediated repair of exocyclic DNA adducts and their derivatives In 2005 two independent groups demonstrated that ε-DNA base lesions such as εAde and εCyt can be also repaired by AlkB proteins [55,56]. AlkBs represent a class of enzymes belonging to non-heme iron superfamily of 2-oxoglutarate- and iron(II)-dependent dioxygenases [57], which oxidize a variety of organic substrates using molecular oxygen and decarboxylating 2-oxoglutarate to succinate [58,59]. AlkB protein from E. coli (EcAlkB) is a member of the adaptive response system to alkylating agents. Homologs of E. coli AlkB are present in many other bacteria and eukaryotes. Some bacteria and eukaryotic species have more than one alkb gene, and they have also been described in plant RNA viruses [60,61]. In mammals nine different AlkB homologs have been identified: ALKBH1-ALKBH8 and a fat massand obesity-associated protein, FTO [62,63]. EcAlkB reverses alkylation damage at N1 position of purines and N3 position of pyrimidines introducted by alkylating agents [64,65]. AlkB proteins catalyze oxidative dealkylation reaction where alkyl group bound to ring nitrogen is hydroxylated by an oxy-ferryl intermediate. The resulting unstable hydroxylalkyl group is next spontaneously released as an appropriate aldehyde, thus leading to regeneration of 4

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shown to repair ε-adducts, εAde, εCyt and 1,N2-εGua in vitro [60]. It was found that the majority of bacterial AlkB proteins tested, similarly to EcAlkB, remove εAde and εCyt from the DNA, and some AlkB proteins can repair the minor, but highly mutagenic 1,N2-εG adduct [74]. Interestingly, some AlkBs exhibit a substantial in vitro repair activity toward ε-lesions, lacking such activity toward methyl lesions [74]. These proteins derive from soil bacteria Xanthomonas campestris, Rhizobium etli and Streptomyces avermitilis, and as such, might be involved in protection of these bacteria from DNA ε-adducts introduced by vinyl chloride, generated in the soil from common industrial solvent, tetrachloroethylene. Tetracholoethylene is a frequent contaminant of groundwater, and was shown to be biotransformed to vinyl chloride [80]. We also revealed that AlkBs from protozoa and mimivirus repair etheno lesions [81]. Human AlkBs, ALKBH2 and ALKBH3, were also found to be active against etheno lesions in vitro. ALKBH2 repairs εAde and εCyt in ds and ssDNA [82,83], and this repair is more efficient when the lesion is located in ds DNA [74]. In dsDNA ALKBH2 repairs also 1,N2-εG adduct [74]. We detected a weak repair activity of ALKBH3 towards εCyt in ssDNA [74]. The ability of recombinant ALKBH2 to remove εAde and εCyt from the DNA suggested that this enzyme could be involved in repair of these lesions in vivo. However, Ringvoll et al., [82] demonstrated that Alkbh2−/− mice, in contrast to Anpg−/− mice, do not accumulate εA in genomic DNA. It is, then, possible that ALKBH2mediated direct reversal of εAde does not play a significant role in repair of endogenously generated εAde, and the main enzyme responsible for removing this lesion from the DNA in vivo is the ANPG glycosylase. Surprisingly, using chemically induced mouse models of colitis Calvo et al. [84] found that not only DNA glycosylase Anpg, but also Alkbh2 and Alkbh3 protect animals from colon cancer. Moreover, the authors showed that deficiency in all three DNA repair enzymes, Anpg, Alkbh2 and Alkbh3 made triple mutant mice unable to recover even from a single administration of dextran sodium sulfate. Since it is well-established that inflammatory processes result in increased level of etheno lesions in the DNA, it is still possible that Alkbh2 and Alkbh3 are involved in removing these lesions from genomic DNA. However, it is clear that more research should be undertaken to elucidate significance of AlkB-mediated repair of etheno-DNA adducts in mammals.

the unmodified base [64,65]. Substrates repaired by EcAlkB are 1methyladenine (1-meA), 3-methylcytosine (3-meC) in ssDNA and dsDNA [64–67], but also from RNA substrates, what suggests a possible role for this proteins in repairing RNA [68,69]. Structurally similar lesions 1-methylguanine (1-meGua) and 3-methylthymine (3-meThy) are also removed by EcAlkB, albeit with less efficiency than 1-meAde and 3-meCyt [66,67]. First human homologs of E. coli AlkB with confirmed repair activity in vitro were ALKBH2 and ALKBH3. ALKBH2 repairs alkylated bases only in the DNA, preferentially in dsDNA, and is more effective in repairing 1-meAde than 3-meCyt [67,68,70]. ALKBH2 is also able to repair methylated DNA in DNA/RNA hybrid but not RNA in such a hybrid [67]. ALKBH3 is active on methylated ssDNA and RNA, and prefers 3-meCyt over 1-meAde [67,68]. ALKBH2 and ALKBH3 are the sole human homologs that complement the hypersensitivity of E. coli alkB mutant to methylating agents [68,70]. However, in vivo activity was confirmed only for ALKBH2 [71], since ALKBH2 null mice, but not ALKBH3-deficient mice, accumulate 1-meA in the genome. ALKBH2 deficient embryonal fibroblasts are hypersensitive to MMS due to inability to remove 1meA from genomic DNA. Interestingly, ALKBH3 has recently been shown to be involved in repair of endogenous 3-meC in genomic DNA. Dango et al. [72] uncovered that ALKBH3 is associated with activating signal cointegrator complex (ASCC), and 3'→5' DNA helicase ASCC3, the largest subunit of this complex, unwinds DNA and thereby generates single-stranded substrate needed for ALKBH3-mediated DNA repair. AlkB proteins repair also bulkier groups, such as ethyl, hydroxyethyl, propyl, hydroxypropyl and highly mutagenic etheno DNA lesions [70,73,74]. By analogy to repair of methylated bases, the etheno bridge of ethenobase is oxidized to epoxide and the product undergoes non-enzymatic hydration to glycol, which is subsequently released as glyoxal (Fig. 4). Repair of etheno-DNA adducts by EcAlkB is more efficient when repaired adduct is positively charged, since this ensures favorable interaction with the negatively charged carboxylic group of Asp135 side-chain in the enzyme active centre [75]. However, in contrast to methyl bases, protonation of etheno-bases occurs at low pH, considerably lower than the physiological pH. This poses a question about AlkB proteins contribution to repair of etheno-adducts in living cells. Studies in E. coli seem to confirm AlkB involvement in repair of etheno-adducts. Purified EcAlkB protein repairs εAde and εCyt in the DNA [55,56,76,77], and reduces mutation frequency, in the same time increasing the survival of CAA-damaged plasmids replicated in E. coli [76,78]. Studying the contribution of known enzymes involved in the repair of ε-adducts, EcAlkB, AlkA glycosylase and Mug glycosylase, Maciejewska et al., [77] concluded that EcAlkB is the main enzyme responsible for repair of εAde in E. coli cells. EcAlkB also repairs 3,N4hydroxyethanocytosine (HEC), a relatively stable intermediate in the formation of εCyt, 3,N4-α-hydroxypropanocytosine, a six-membered acrolein adduct and 1, N6-ethanoadenine, the lesion formed in the reaction of DNA with the antitumor agent 1,3-bis(2-chloroethyl)-1nitrosourea [76,77,79]. Several other bacterial AlkB proteins were

4. Repair of bulky exocyclic DNA adducts 4.1. Nucleotide excision repair Nucleotide excision repair is associated with removal of bulky, structure-pertrubing DNA adducts, such as ultraviolet radiation induced cyclobutane pyrimidine dimers, or polycyclic aromatic hydrocarbons [85]. However, NER can also correct smaller modified bases, among others those deriving from the addition of LPO products to the DNA. There are two sub-pathways of NER system activity: (i) slow, global genome repair (GGR) and (ii) fast, transcription-coupled repair (TCR), which participates only in repair of active genes. The mechanism of these two sub-pathways is similar except for damage recognition step. O

O

AlkB

N

2+

N

N

Fe

N

CH CH

glyoxal

O

N

NH2 N

N

N N N

N

2OG O2

dR

dA

succinate CO2

N

N

N

dR

dR

epoxide

dA

Fig. 4. The mechanism of AlkB-mediated DNA repair through oxidative dealkylation of εAde.

5

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In GGR, UvrA protein of E. coli or mammalian excision repair nuclease XPC-HR23B protein heterodimer together with XPA protein specifically recognize and bind DNA lesions [86]. In TCR, lesion present on the transcribed strand constitutes a block to RNA polymerase II that represents a signal initiating the repair process or inducing apoptosis [87–89]. In E. coli, the transcription repair coupling factor is encoded by the mfd gene [90] and requires the participation of all the bacterial excision repair Uvr, A, B, and C proteins. In humans, recognition step in TCR is dependent on Cockayne syndrome complementation group B (CSB) and group A (CSA) proteins as well as on XPA protein [91,92]. After the recognition steps in both NER sub-pathways, the UvrA2B complex of E. coli or the two mammalian helicases XPB and XPD open up the DNA around the lesion and allow incisions to be introduced on both sides of the damage by endonucleases, UvrABC (E. coli) or XPFERCC1 and XPG (mammals). This is followed by removal of the 11–13mer (E. coli) or 24–32-mer (mammals) oligodeoxynucleotide containing damage, and filling of the resulting gap by the replicative DNA polymerase III, or δ and ε, and ligation to the parental strand by DNA ligase [37,85]. NER is the major pathway responsible for removing from the DNA such exocyclic adducts as M1dG and 1,N2-propano-dG [93,94]. Also, HNE-DNA adducts are the substrate of NER in E. coli [32] and in mammalian cell extract [95]. In E. coli the survival of HNE-modified M13 phage decreased drastically when replicated in uvrA deficient strain in comparison to the wild type bacteria, and mutation frequency increased. Interestingly, in the single uvrA mutant recombination events constituted 48% of all mutations, which suggests that recombination is as important repair pathway for removing HNE-DNA adducts in E. coli as NER [32]. Both in bacteria and in human cells HNE-DNA adducts constitute a block for RNA polymerases, and trigger fast TCR subpathway [31]. Human CSB-deficient cells were shown to be hypersensitive to physiological concentrations of HNE (1–10 μM). Treatment of the wild type cells with 1–20 μM HNE caused dephosphorylation of the CSB protein. Such dephosphorylation stimulates its ATPase activity necessary for TCR. Cell lines expressing CSB protein mutated in different ATPase domains exhibited different sensitivities to HNE. Motif II mutant, which binds ATP, but is totally defective in ATP hydrolysis was as sensitive to HNE as CSB-null cells. In contrast, motif V mutant cells were as sensitive to HNE as the cells bearing wild type protein, while motif VI mutant cells showed intermediate sensitivity to HNE. These mutants exhibited decreased ATP binding, but retained residual ATPase activity. In response to HNE CSB deficient cells developed a higher level of sister chromatid exchanges in comparison to the wild type cells. The latter observation suggests that also in mammalian cells homologous recombination is important repair pathway for bulky LPO-derived HNE-DNA adducts.

dependent increase of number of cells with micronuclei and chromosomal aberrations was observed. Furthermore, statistically significant increase of the level of sister chromatid exchange (SCE) in cells after HNE treatment was found. Induction of SCE in cells results from homologous recombination. HNE also caused activation of SOS system [101], NER and recombination in Escherichia coli [32]. Identification of point and tandem mutations in bacteria, may suggest induction of DNA crosslinks [102]. Addition of aldehyde group of HNE to nucleobases is reversible and liberated reactive aldehyde group can form a Schiff bond to the amino group of opposite or adjacent DNA bases. Finally, intra- or interstrand DNA-DNA crosslinks (ICLs) are formed [103,104]. ICLs are the most toxic DNA damages for cells and constitute 1–5% of all monoadducts and intracrosslinks induced by crosslinking agents [105]. Detection and separation of 1–2% of HNE-mediated crosslinks from all DNA adducts fraction in 4-hydroxynonenal treated calf thymus DNA was reported [104]. However, enals-mediated crosslinks are unstable and bulky N2-dG adducts, as NER substrates, can be effectively reversed [106]. In mammalian cells, DNA crosslinks are processed by multiple proteins from different repair pathways including NER, TLS, HR and Fanconi Anemia pathway (FA) [107].

4.2. Homologous recombination

DNA repair plays an important role in protecting individuals from cancer. Our study on etheno DNA adducts and repair capacity in lung cancer showed impaired repair of εAde and εCyt in patients developing the adenocarcinoma type of lung tumor, the etiology of which is linked to inflammatory processes. For this reason, we postulated that lipid peroxidation was more important in the pathogenesis of lung adenocarcinoma than in the other type of non-small cell lung carcinoma (NSCLC), squamous cell carcinoma, and that deficiency of εAde and εCyt repair may be a risk factor in the development of this disease [110]. Also repair of exocyclic DNA adducts (εAde and εCyt) was decreased in leukocytes of colon cancer patients in comparison to healthy controls. Interestingly, no mutations were found within the whole sequence of εAde and εCyt DNA glycosylases, neither decreased mRNA level of these enzymes was found. However, in colon tumor tissue repair activity was significantly increased in comparison to histologically unchanged, normal colon [111]. These results pointed to the importance of repair of lipid peroxidation induced DNA damage in the pathology of inflammation related colon cancer, as well as suggested that post-translational mechanisms modulating repair rate of

4.3. Translesion synthesis Studies of the role of damage-specific DNA polymerases in the bypass of bulky HNE-DNA adducts in E. coli have been performed using M13 phage, which replicated in uvrA-E. coli strains carrying one, two or all three SOS DNA polymerases [33]. It was observed that Pol V can infrequently bypass HNE-DNA adducts inducing mutations at Gua, Cyt and Ade sites, while bypass by Pol IV and Pol II was error-free. PolIV bypassed these adducts with high efficiency, but Pol II only infrequently. Studies of the bypass of HNE-DNA adducts by purified mammalian TLS polymerases showed that they constitute a strong block for most studied proteins. However, similarly to E. coli enzymes, cooperation of specific TLS polymerases caused error-free bypass. Pol ι was able to incorporate correctly matched nucleotide opposite the HNE-dG adduct, although it was not able to elongate the synthesized DNA strand and fell off the template. Pol κ, in turn, could elongate the HNE-dG:dC pair, which ensured further DNA synthesis [108]. In this way the HNE-dG adducts were bypassed by two damage-specific DNA polymerases in an error-free manner. This may, at least partially explain the fact that HNE is the least mutagenic LPO product, however due to the fact that it is also able to modify proteins, the most cytotoxic [109]. 5. Modulation of exocyclic DNA adducts repair and human diseases

Bulky DNA adducts induced by LPO products arrest replication fork progression [96]. This may cause generation of single strand breaks (SSBs), which, if unrepaired, may subsequently be transformed into double strand breaks (DSBs) [97]. DSBs can also result from unfinished repair of bulky LPO-DNA adducts by NER, e.g. when NER processing is concomitant with replication. One of cellular markers of DSB is histone H2A.X phosphorylation. It was shown that after treatment of cells with HNE H2A.X is being phosphorylated. This H2A.X activation corresponded with nucleoid relaxation, which was detected in neutral comet assay [98]. Moreover in HepG2 cells activation of DNA damage response (DDR) signaling induced by replicative stress was also observed and G2/M phase arrest for repair of DNA breaks reported [98]. Summarizing, HNE can induce formation of DSB in mammalian cells. Double strand breaks are toxic for cells and are repaired by recombination pathways (homologous recombination and non-homologous end joining (NHEJ). Karlhuber et al. [99] and Eckl et al. [100] showed genotoxic effect of 4-hydroxynonenal in cells. HNE dose 6

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function, contributing to features and diseases associated with premature senescence [126]. In line with these results, elevated oxidative stress and subsequent deficiency of enzymatic activity via LPO modification may impair exocyclic DNA adducts repair, and these functional defects may be responsible for aberrant phenotypes and diseases. Further studies on specific interactions of LPO modified enzymes with various target proteins may provide clues to the mechanisms responsible for such a global effect of LPO on various cellular processes.

oxidatively damaged DNA may be important factor in cancer pathology. LPO products react more efficiently with proteins than with the DNA. Thus protein modification most likely represents one of the main mechanisms by which LPO influences physiological as well as pathological processes [112]. For example, HNE is an electrophile due to its three functional groups that react with nucleophilic amino acid residues of proteins forming covalent adducts with protein nucleophilic side chains. HNE reaction with the thiol group of cysteine, the primary amino-group of lysine or the imidazole group of histidine leads to formation of stable Michael addition adducts with a hemiacetal structure [105]. The nucleophilic attack by thiol or amino groups occurs primarily at carbon 3 and secondly at the carbonyl carbon 1. In most cases adduction of HNE to proteins leads to the inhibition of protein biological activity. For example, we showed that the ATPase activity of Cockayne syndrome group B protein was abolished after preincubation with 200 µM HNE [31]. Accordingly, Schwarzer et al. found that formation of HNE–protein kinase C (PKC) adduct after treatment of human monocytes with 10–100 µM HNE totally inhibited PKC activity [113]. Higher doses of HNE (150–300 µM) were needed to inactivate 50% activity of microsomal glucose-6-phosphatase [114]. In the case of Hsp72 or Hsp90, the modification of very sensitive critical thiols by physiologically relevant concentrations of HNE (10 µM and 45 µM, respectively) impaired protein binding and ATPase activity [115,116]. The exposure of purified human SIRT3 to 100 µM HNE resulted in about 75% inhibition [117]. Also treatment of recombinant human Akt2 with 20 or 40 μM HNE inhibited Akt2 activity by 30 or 85%, respectively [118]. Furthermore, it has been demonstrated that HNEinduced cellular senescence in leukemic cell lines by inhibiting telomerase activity [119]. Moreover, adduction by HNE made protein more susceptible to proteolysis by the proteasomal pathway [120]. However, despite overwhelming data showing impairment of catalytic activity of HNE modified proteins, in some cases formation of HNEprotein adducts can have an activating effect. Low concentrations of HNE (1–10 µM) stimulated the activity of phosphoinositide-specific phospholipase C [121]. Our results showed that HNE also modified the activity of the BER system. HNE inhibited in vitro the activity of purified ANPG and TDG glycosylases excising from the DNA εAde and εCyt, but not of APE1 endonuclease and 8-oxoGua-DNA glycosylase 1 (OGG1). Nevertheless, K21 cells pretreated with physiological HNE concentrations were more sensitive to oxidative and alkylating agents, H2O2 and MMS, when compared to untreated cells. Detailed examination of HNE influence on particular stages of BER in K21 cells revealed that HNE may decrease the rate of εAde and εCyt excision, but not that of 8-oxoGua. Simultaneously HNE increased the rate of AP site incision and blocked the re-ligation step after the gap-filling by DNA polymerases. We have also found that HNE pretreatment of cells, which were subsequently exposed to H2O2 or MMS increased the level of poly(ADP-ribose) foci, which appear in cells in response to SSBs. These results suggest that LPO products act not only by forming DNA adducts, but also have the ability to deregulate activities of BER enzymes, and increase the level of unrepaired DNA breaks [122]. Others have also shown that HNE inhibits the activity of NER system in human cells [123]. Our further studies showed that HNE can modulate the activity of another DNA processing enzyme, Werner (WRN) helicase/exonuclease. Lack of WRN causes hereditary disease associated with chromosomal instability, premature aging and cancer predisposition. Werner protein appears to participate in the cellular response to oxidative stress and cells devoid of WRN display elevated levels of oxidatively generated DNA damage [124,125]. We demonstrated that the Werner protein undergoes HNE adduction in vitro, but also in living cells [126]. Such in vitro WRN modification was associated with modulation of ATPdependent unwinding activity and abolishment of fork substrate degradation, as well as ATP hydrolysis. In light of the obtained results, we postulated that HNE adduction to WRN was a post-translational modification, which might affect WRN conformational stability and

6. Beyond repair functions of enzymes removing exocyclic DNA adducts Several DNA repair proteins perform additional functions beyond DNA repair. Thus, inactivation of their activity by mutations or posttranslational modifications has wide consequences on functioning of cells and whole organisms. 6.1. TDG and MBD4 DNA glycosylases Human enzymes participating in repair of exocyclic DNA adducts display several other functions. It is probable that the main function of TDG and MBD4 glycosylases is regulation of DNA methylation status in gene promoters by their involvement in active demethylation. This problem is described in detail by Klungland and Robertson in this issue. TDG glycosylase also plays a role as direct regulator of transcription factors and signal transduction. TDG directly interacts with retinoic acid (RA) receptors RAR/RXR. In the absence of retinoic acid TDG binds to RARα and RXR and stimulates binding of these receptors to gene promoters, where they subsequently bind co-repressors NCOR1, SMRT (NCOR2), and this results in the inhibition of transcription of genes regulated by RAR/RXR [127]. In this way deficiency of vitamin A, which results in augmentation of pro-proliferative signalization is potentiated by TDG protein. Another activity of TDG, which may trigger cell growth and proliferation is activation of WNT pathway. TDG binds to β-catenin/TCF/LEF1/CBP complex, and this potentiates activation of histone acetylase at promoter sites of genes activated by WNT pathway, and stimulates cell growth and proliferation [128]. TDG and β-catenin are overexpressed in colon cancer. This facilitates cell proliferation due to removal of DNA damage on one hand, and on the other activation of pro-proliferative signalization [128]. It was also shown that TDG glycosylase potentiates transcription of estrogenregulated genes through direct interaction with estrogen receptor alpha [129]. Expression of TDG glycosylase is, however, important also for the treatment of colon cancer, in which 5-fluorouracil (5FU) is used as a routine chemotherapeutic. 5FU is incorporated into the DNA, however its cytotoxicity is dependent on TDG activity [130]. Additionally, TDG interacts and co-activates proteins from TP53 family, and in this way promotes apoptosis [131]. Overexpression of TDG activity observed by us in colon and lung tumor tissues [110,111] might play contradictory roles in progression and treatment of cancer. 6.2. APE1 APE1, was reported to reveal several non-repair enzymatic and regulatory activities, such as: transcription regulation, apoptosis, telomere maintenance, and rRNA synthesis [146–152]. APE1, called also Ref1 (Redox effector factor-1) influences gene expression via two independent mechanisms. One is unique to the human system and is linked to controlling the redox status of a subset of transcription factors (TRs) including: FOS-JUN heterodimer, JUN homodimer, CREB, AP-1, p53, ATF-1, ATF-2, p65-NF-kappaB, HIF-1α, PAX and Myb [153]. It is believed that APE1 N-terminal part, responsible for enzyme redox activity, reduces cysteines present in DNA binding motifs of TRs. This increases their affinity to promoters of regulated genes. The wide spectrum of TRs regulated by APE1 makes it 7

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ALKBH8-mediated tRNA modifications are regulators of cellular oxidative stress responses [141]. ALKBH8 silencing reduced ROS production via down-regulation of NOX-1 and induced apoptosis through activation of c-Jun N-terminal kinase (JNK) and p38. Depletion of ALKBH8 significantly suppressed invasion, angiogenesis, and growth of bladder cancers in mice [142]. FTO and ALKBH5 are RNA demethylases responsible for oxidative demethylation of N6-methyladenosine (6-meA) [136,137,143]. In eukaryotic messenger RNA 6-meAde is one of the most abundant modifications. In mammals, one mRNA molecule contains approximately from 3 to 5 residues of 6-meAde in a consensus sequence Pu[G > A]m6AC[A/C/U] [144]. 6-meAde is introduced into mRNA by methyltransferase complex consisting of three subunits: METTL3 (Methyltransferase-like protein 3), METTL14 (Methyltransferase-like protein 14) and WTAP (Wilms tumor 1-associating protein) [144]. Recent discoveries suggest that 6-meAde plays a role in epigenetic regulation of mRNA by influencing transcription, splicing, nuclear export, localization, translation, and mRNA stability. Complex importance of 6-meAde is highlighted by the fact that it regulates the fate of embryonic stem cells (ESCs) and circadian clock in mammals [145,146]. Many groups found a strong correlation between a single nucleotide polymorphism in the first intron of FTO gene and increased body mass index and obesity risk [147–150], which suggests involvement of FTO in energy homeostasis and metabolism [151–153]. It has been shown that FTO in vitro repairs 3-meThy, 3-meUra and 6-meAde in singlestranded DNA and RNA, but the physiological substrate and exact function of FTO remained unknown [154,155]. In 2011 Jia et al. [136] reported that FTO demethylates 6-meAde in RNA in vitro, and siRNAmediated FTO silencing increases, whereas its overexpression reduces the level of 6-meAde in mRNA. FTO oxidizes 6-meA to N6-hydroxymethyladenosine and N6-formyladenosine in a step-wise manner [143]. Recently also ALKBH5 was found to catalyze oxidative demethylation of 6-meAde in mRNA [143].mRNA samples isolated from different organs of Alkbh5-deficient mice had increased level of 6-meAde. Alkbh5-deficient male mice displayed impaired fertility due to apoptosis of pachytene and metaphase-stage spermatocytes and aberrant spermiogenesis [137]. It was reported that ALKBH5 gene is regulated via hypoxia by hypoxia inducible factor-1 (HIF-1) [156]. Growing breast cancer cells under hypoxia led to HIF-1α- and HIF-2α-dependent increase in ALKBH5 expression, and enhancement of mRNA stability of pluripotency factor NANOG through ALKBH5-mediated oxidative demethylation of 6-meAde in the 3'-UTR of NANOG [156]. AlkB enzymes are also involved in demethylation of proteins. ALKBH1 is proposed to be histone H2A dioxygenase [138], although a lot of contradictory data about activity of ALKBH1 have been published. It has been suggested that ALKBH1 is a mitochondrial protein demethylating 3-meCyt in single-stranded DNA and RNA in vitro or it exhibits DNA lyase activity at abasic sites [157,158], or participates in gene regulation during spermatogenesis and its lack impairs placental trophoblast lineage differentiation [158]. Recently, it was demonstrated that ALKBH1 is involved in neural development and influences methylation status of histone H2A via its hydroxylation [138]. ALKBH1 was found to be involved in regulation of pluripotency and differentiation of embryonic stem cells (ESCs) through interaction with the core transcriptional pluripotency network [159]. ALKBH4 was found to interact with proteins involved in regulation of gene expression or chromatin state [160]. It was demostrated [139] that ALKBH4 catalyses demethylation of a monomethylated lysine residue (K84) in actin. Through actin demethylation, ALKBH4 regulates actin-myosin II interaction as myosin II is recruited and interacts only with unmethylated form of actin. Deletion of ALKBH4 is embryonically lethal as it leads to defects in actomyosin-dependent processes such as cytokinesis and cell motility [139]. Recent studies, using inducible Alkbh4 knockout mice, revealed that ALKBH4 is localized in nucleolar structures in spermatogenic and Sertoli cells, and deficiency of ALKBH4

an important protein responsible for 'fine tuning' of several development processes and cancer progression [145,146]. The second mechanism of transcription regulation by APE1 is performed by its binding to promoters containing a calcium responsive sequence element (CaRE) in complex with XRCC5/XRCC6 (Ku80/Ku70) and hnRNP-L proteins [154]. Around 57 genes involved in DNA damage response, gene expression regulation, cell growth and other cellular processes might be regulated by this mechanism. APE1 binding to promoters is enhanced by p300/CBP-mediated acetylation [155] and inhibited by SIRT deacethylase [156]. Case studies have confirmed binding of APE1 to promoters of renin [157], Bax [158], SIRT [156], APE1 [159] and PTH genes [155], which can result in both promoter repression (e.g. PTH) or activation (e.g. SIRT). APE1 also regulates apoptosis by different mechanisms. APE1 is part of the SET-complex located in the endoplasmic reticulum, which is the main target of granzyme A (GzmA), a protease introduced to a tumor or virus infected cells by cytotoxic lymphocytes T and natural killer cells. Upon cleavage of SET-subunits, HMG2 and APE1, NME1 subunit is released and translocates to the nucleus where it mediates genome fragmentation [160,161]. Interestingly, APE1 is also localized in mitochondria, where it protects the cell from apoptosis possibly by influencing the redox state of the mitochondrial transcription factor A TFAM [162]. APE1 has also been shown to be involved in telomere maintenance. Knock-down of APE1 causes the dissociation of TRF2 (TERF2) from telomere repeat. TRF2 is important for preventing end-to-end fusion of chromosome ends. Accordingly, telomere length is reduced in APE1 deficient cells [164]. Interestingly, in vitro studies showed that APE1 can cleave a wide range of ssRNAs [163,165,166]. It also shows 3' RNA phosphatase and a weak 3'→5' exoribonuclease activity [167]. The catalytic site for RNA and DNA endonuclease cleavage overlap only partially and is located in the protein C-terminus. For RNA cleavage the enzyme does not require Mg2+ ions [166]. Despite these data the in vivo function of APE1 in mRNA and rRNA metabolism is yet poorly described. Direct interaction of APE1 with proteins involved in rRNA metabolism (RLA0, NPM1, MEP50/WDR77, RSSA and PRP19), and APE1 translocation to nucleous in response to interaction with nucleophosmin (NPM1) [151] suggest that APE1 participates in rRNA maturation and/or degradation. 6.3. AlkB proteins Additional functions of AlkB proteins were recently found. They include: modification of tRNA [132–135], oxidative demethylation of N6-methyladenine in mRNA [136,137], and demethylation of lysine in histone H2A and actin [138,139]. ALKBH8 is involved in synthesis of modified uridine at positions 34 (the wobble position) in tRNA. The enzyme contains not only the Fe(II)/2OG oxygenase domain but also N-terminal RNA binding domain (RRM) and a C-terminal methyltransferase domain (MT), which is similar to tRNA methyltransferase, Trm9 from S. cerevisiae. MT domain of ALKBH8 forms a heterodimeric complex with a small accessory protein TRM112, and this complex catalyses formation of 5-methoxycarbonylmethyluridine (mcm5U) modification of the wobble uridine in many tRNAs [132,133]. RRM/AlkB domain of ALKBH8 is responsible for subsequent hydroxylation of mcm5U into (S)-5-methoxycarbonylhydroxymethyluridine ((S)-mchm5Ura), but only in tRNAGly(UCC) [134,135]. Modifications at wobble position influence mainly the decoding properties of the tRNA [140]. Additionally, incorporation of selenocysteine requires recoding of the UGA stop by selenocysteine tRNA (tRNAUGA-SEC) containing mcm5U and 5-methoxycarbonylmethyl2'-O-methyluridine (mcm5Um) modifications at the wobble position [132]. In response to oxidative stress, the level of ALKBH8 and mcm5Um in tRNA increase to drive the expression of ROS detoxification enzymes containing selenocysteine, such as glutathione peroxidases and thioredoxin reductases. These findings suggest that ALKBH8 and 8

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