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Abstract: Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, represent a major form of DNA damage in cells. The repair of alkylation damage is critical in all cells because such damage is cytotoxic and potentially mutagenic. Alkylation chemotherapy is a major therapeutic modality for many tumors, underscoring the importance of the repair pathways in cancer cells. Several different pathways exist for alkylation repair, including base excision and nucleotide excision repair, direct reversal by methyl-guanine methyltransferase (MGMT), and dealkylation by the alkB homolog (ALKBH) protein family. However, maintaining a proper balance between these pathways is crucial for the favorable response of an organism to alkylating agents. Here, we summarize the progress in the field of DNA alkylation lesion repair and describe the implications for cancer chemotherapy.

DNA烷基化损伤修复及其在肿瘤化疗中的意义

概要：DNA烷基化损伤作为细胞内一种主要的DNA损伤形式，可由外源性化学试剂和内源性代谢物诱导发生。DNA烷基化损伤具有细胞毒性并可能诱导突变，因此烷基化损伤修复在所有细胞内都至关重要。同时，烷基化肿瘤化学疗法是许多肿瘤的主要治疗方案，这也强调了癌细胞内烷基化修复途径的重要性。烷基化修复的途径包括碱基切除和核苷酸切除修复、甲基鸟嘌呤甲基转移酶（MGMT）的直接逆转以及ALKBH蛋白家族的脱烷基化作用。然而，这些修复途径之间的内部平衡才是机体有效应答DNA烷基化试剂的关键所在。在这里，我们总结了DNA烷基化损伤修复领域的进展，并进一步描述该领域的研究对肿瘤化疗的深刻意义。

关键词：DNA烷基化修复；碱基切除修复；甲基鸟嘌呤甲基转移酶（MGMT）；ALKBH

[1]AasPA, OtterleiM, FalnesP脴, et al., 2003. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature, 421(6925):859-863.

[2]AsagoshiK, LiuY, MasaokaA, et al., 2010. DNA polymerase 尾-dependent long patch base excision repair in living cells. DNA Repair (Amst), 9(2):109-119.

[3]BapatA, FishelML, KelleyMR, 2009. Going Ape as an approach to cancer therapeutics. Antioxid Redox Signal, 11(3):651-667.

[4]BapatA, GlassLS, LuoMH, et al., 2010. Novel small-molecule inhibitor of apurinic/apyrimidinic endonuclease 1 blocks proliferation and reduces viability of glioblastoma cells. J Pharmacol Exp Ther, 334(3):988-998.

[5]BarrowsLR, MageePN, 1982. Nonenzymatic methylation of DNA by S-adenosylmethionine in vitro. Carcinogenesis, 3(3):349-351.

[6]BeranekDT, 1990. Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agents. Mutat Res, 231(1):11-30.

[7]Bj酶r氓sK脴, SousaMML, SharmaA, et al., 2017. Monitoring of the spatial and temporal dynamics of BER/SSBR pathway proteins, including MYH, UNG2, MPG, NTH1 and NEIL1-3, during DNA replication. Nucleic Acids Res, 45(14):8291-8301.

[8]BobolaMS, FinnLS, EllenbogenRG, et al., 2005. Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors. Clin Cancer Res, 11(20):7405-7414.

[9]BricknerJR, SollJM, LombardiPM, et al., 2017. A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. Nature, 551(7680):389-393.

[10]BricknerJR, TownleyBA, MosammaparastN, 2019. Intersections between transcription-coupled repair and alkylation damage reversal. DNA Repair (Amst), 81:102663.

[11]ButlerM, PongorL, SuYT, et al., 2020. MGMT status as a clinical biomarker in glioblastoma. Trends Cancer, 6(5):380-391.

[12]CalvoJA, MeiraLB, LeeCYI, et al., 2012. DNA repair is indispensable for survival after acute inflammation. J Clin Invest, 122(7):2680-2689.

[13]ChenFY, BianK, TangQ, et al., 2017. Oncometabolites D- and L-2-hydroxyglutarate inhibit the AlkB family DNA repair enzymes under physiological conditions. Chem Res Toxicol, 30(4):1102-1110.

[14]ChenZJ, QiMJ, ShenB, et al., 2019. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res, 47(5):2533-2545.

[15]ChristmannM, VerbeekB, RoosWP, et al., 2011. O⁶-methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: enzyme activity, promoter methylation and immunohistochemistry. Biochim Biophys Acta, 1816(2):179-190.

[16]CoquerelleT, DoschJ, KainaB, 1995. Overexpression of N-methylpurine-DNA glycosylase in Chinese hamster ovary cells renders them more sensitive to the production of chromosomal aberrations by methylating agents鈥攁 case of imbalanced DNA repair. Mutat Res, 336(1):9-17.

[17]CorbettMA, Dudding-BythT, CrockPA, et al., 2015. A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A. J Med Genet, 52(4):269-274.

[18]DaiXX, WangTL, GonzalezG, et al., 2018. Identification of YTH domain-containing proteins as the readers for N1-methyladenosine in RNA. Anal Chem, 90(11):6380-6384.

[19]DangoS, MosammaparastN, SowaME, et al., 2011. DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation. Mol Cell, 44(3):373-384.

[20]DeansAJ, WestSC, 2011. DNA interstrand crosslink repair and cancer. Nat Rev Cancer, 11(7):467-480.

[21]de MurciaJM, NiedergangC, TruccoC, et al., 1997. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA, 94(14):7303-7307.

[22]DominissiniD, NachtergaeleS, Moshitch-MoshkovitzS, et al., 2016. The dynamic N¹-methyladenosine methylome in eukaryotic messenger RNA. Nature, 530(7591):441-446.

[23]Drabl酶sF, FeyziE, AasPA, et al., 2004. Alkylation damage in DNA and RNA鈥攔epair mechanisms and medical significance. DNA Repair (Amst), 3(11):1389-1407.

[24]DumencoLL, AllayE, NortonK, et al., 1993. The prevention of thymic lymphomas in transgenic mice by human O6-alkylguanine-DNA alkyltransferase. Science, 259(5092):219-222.

[25]DumitracheLC, ShimadaM, DowningSM, et al., 2018. Apurinic endonuclease-1 preserves neural genome integrity to maintain homeostasis and thermoregulation and prevent brain tumors. Proc Natl Acad Sci USA, 115(52):E12285-E12294.

[26]DuncanT, TrewickSC, KoivistoP, et al., 2002. Reversal of DNA alkylation damage by two human dioxygenases. Proc Natl Acad Sci USA, 99(26):16660-16665.

[27]EngelwardBP, WeedaG, WyattMD, et al., 1997. Base excision repair deficient mice lacking the aag alkyladenine DNA glycosylase. Proc Natl Acad Sci USA, 94(24):13087-13092.

[28]EstellerM, Garcia-FoncillasJ, AndionE, et al., 2000. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med, 343(19):1350-1354.

[29]FanJS, WilsonPF, WongHK, et al., 2007. XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells. Environ Mol Mutagen, 48(6):491-500.

[30]FengJA, CrastoCJ, MatsumotoY, 1998. Deoxyribose phosphate excision by the N-terminal domain of the polymerase 尾: the mechanism revisited. Biochemistry, 37(27):9605-9611.

[31]FuD, CalvoJA, SamsonLD, 2012. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer, 12(2):104-120.

[32]FuD, SamsonLD, H眉bscherU, et al., 2015. The interaction between ALKBH2 DNA repair enzyme and PCNA is direct, mediated by the hydrophobic pocket of PCNA and perturbed in naturally-occurring ALKBH2 variants. DNA Repair (Amst), 35:13-18.

[33]FuSJ, LiZ, XiaoLB, et al., 2019. Glutamine synthetase promotes radiation resistance via facilitating nucleotide metabolism and subsequent DNA damage repair. Cell Rep, 28(5):1136-1143.e4.

[34]FukushimaT, KatayamaY, WatanabeT, et al., 2005. Promoter hypermethylation of mismatch repair gene HMLH1 predicts the clinical response of malignant astrocytomas to nitrosourea. Clin Cancer Res, 11(4):1539-1544.

[35]GentilA, Cabral-NetoJB, Mariage-SamsonR, et al., 1992. Mutagenicity of a unique apurinic/apyrimidinic site in mammalian cells. J Mol Biol, 227(4):981-984.

[36]GermanoG, LambaS, RospoG, et al., 2017. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature, 552(7683):116-120.

[37]GilljamKM, FeyziE, AasPA, et al., 2009. Identification of a novel, widespread, and functionally important PCNA-binding motif. J Cell Biol, 186(5):645-654.

[38]GlassnerBJ, WeedaG, AllanJM, et al., 1999. DNA repair methyltransferase (MGMT) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents. Mutagenesis, 14(3):339-347.

[39]HegiME, DiserensAC, GorliaT, et al., 2005. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med, 352(10):997-1003.

[40]HochNC, HanzlikovaH, RultenSL, et al., 2017. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature, 541(7635):87-91.

[41]HofsethLJ, KhanMA, AmbroseM, et al., 2003. The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation. J Clin Invest, 112(12):1887-1894.

[42]HongHZ, CaoHC, WangYS, 2007. Formation and genotoxicity of a guanine-cytosine intrastrand cross-link lesion in vivo. Nucleic Acids Res, 35(21):7118-7127.

[43]HoriH, 2014. Methylated nucleosides in tRNA and tRNA methyltransferases. Front Genet, 5:144.

[44]HortonJK, Joyce-GrayDF, PachkowskiBF, et al., 2003. Hypersensitivity of DNA polymerase 尾 null mouse fibroblasts reflects accumulation of cytotoxic repair intermediates from site-specific alkyl DNA lesions. DNA Repair (Amst), 2(1):27-48.

[45]HunterC, SmithR, CahillDP, et al., 2006. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res, 66(8):3987-3991.

[46]HuttlinEL, BrucknerRJ, PauloJA, et al., 2017. Architecture of the human interactome defines protein communities and disease networks. Nature, 545(7655):505-509.

[47]JacobsAL, Sch盲rP, 2012. DNA glycosylases: in DNA repair and beyond. Chromosoma, 121(1):1-20.

[48]JaiswalAS, BanerjeeS, PandaH, et al., 2009. A novel inhibitor of DNA polymerase 尾 enhances the ability of temozolomide to impair the growth of colon cancer cells. Mol Cancer Res, 7(12):1973-1983.

[49]JaiswalAS, BanerjeeS, AnejaR, et al., 2011. DNA polymerase 尾 as a novel target for chemotherapeutic intervention of colorectal cancer. PLoS ONE, 6(2):e16691.

[50]JelezcovaE, TrivediRN, WangXH, et al., 2010. Parp1 activation in mouse embryonic fibroblasts promotes Pol 尾-dependent cellular hypersensitivity to alkylation damage. Mutat Res, 686(1-2):57-67.

[51]JiangJ, ZhangXQ, YangHM, et al., 2009. Polymorphisms of DNA repair genes: ADPRT, XRCC1, and XPD and cancer risk in genetic epidemiology. In: Verma M (Ed.), Cancer Epidemiology. Humana Press, New York, p.305-333.

[52]JohnsonRE, YuSL, PrakashS, et al., 2007. A role for yeast and human translesion synthesis DNA polymerases in promoting replication through 3-methyl adenine. Mol Cell Biol, 27(20):7198-7205.

[53]KainaB, ChristmannM, NaumannS, et al., 2007. MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst), 6(8):1079-1099.

[54]KawateH, ItohR, SakumiK, et al., 2000. A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice. Carcinogenesis, 21(2):301-305.

[55]KietrysAM, VelemaWA, KoolET, 2017. Fingerprints of modified RNA bases from deep sequencing profiles. J Am Chem Soc, 139(47):17074-17081.

[56]KlapaczJ, MeiraLB, LuchettiDG, et al., 2009. O⁶-methylguanine-induced cell death involves exonuclease 1 as well as DNA mismatch recognition in vivo. Proc Natl Acad Sci USA, 106(2):576-581.

[57]KlapaczJ, LingarajuGM, GuoHH, et al., 2010. Frameshift mutagenesis and microsatellite instability induced by human alkyladenine DNA glycosylase. Mol Cell, 37(6):843-853.

[58]KonishiN, NakamuraM, IshidaE, et al., 2005. High expression of a new marker PCA-1 in human prostate carcinoma. Clin Cancer Res, 11(14):5090-5097.

[59]LarsonK, SahmJ, ShenkarR, et al., 1985. Methylation-induced blocks to in vitro DNA replication. Mutat Res, 150(1-2):77-84.

[60]LiXY, XiongXS, WangK, et al., 2016. Transcriptome-wide mapping reveals reversible and dynamic N¹-methyladenosine methylome. Nat Chem Biol, 12(5):311-316.

[61]LinDP, WangYX, SchererSJ, et al., 2004. An Msh2 point mutation uncouples DNA mismatch repair and apoptosis. Cancer Res, 64(2):517-522.

[62]LindahlT, 1993. Instability and decay of the primary structure of DNA. Nature, 362(6422):709-715.

[63]LiuL, AllayE, DumencoLL, et al., 1994. Rapid repair of O⁶-methylguanine-DNA adducts protects transgenic mice from N-methylnitrosourea-induced thymic lymphomas. Cancer Res, 54(17):4648-4652.

[64]LiuLL, GersonSL, 2004. Therapeutic impact of methoxyamine: blocking repair of abasic sites in the base excision repair pathway. Curr Opin Investig Drugs, 5(6):623-627.

[65]LiuY, PrasadR, WilsonSH, 2010. HMGB1: roles in base excision repair and related function. Biochim Biophys Acta, 1799(1-2):119-130.

[66]LuoCY, HajkovaP, EckerJR, 2018. Dynamic DNA methylation: in the right place at the right time. Science, 361(6409):1336-1340.

[67]McFaline-FigueroaJL, BraunCJ, StanciuM, et al., 2015. Minor changes in expression of the mismatch repair protein MSH2 exert a major impact on glioblastoma response to temozolomide. Cancer Res, 75(15):3127-3138.

[68]MehtaKPM, LovejoyCA, ZhaoRX, et al., 2020. HMCES maintains replication fork progression and prevents double-strand breaks in response to APOBEC deamination and abasic site formation. Cell Rep, 31(9):107705.

[69]MeiraLB, BugniJM, GreenSL, et al., 2008. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Invest, 118(7):2516-2525.

[70]MohanM, AkulaD, DhillonA, et al., 2019. Human RAD51 paralogue RAD51C fosters repair of alkylated DNA by interacting with the ALKBH3 demethylase. Nucleic Acids Res, 47(22):11729-11745.

[71]MohniKN, WesselSR, ZhaoRX, et al., 2019. HMCES maintains genome integrity by shielding abasic sites in single-strand DNA. Cell, 176(1-2):144-153.e13.

[72]MojasN, LopesM, JiricnyJ, 2007. Mismatch repair-dependent processing of methylation damage gives rise to persistent single-stranded gaps in newly replicated DNA. Genes Dev, 21(24):3342-3355.

[73]MontaldoNP, BordinDL, BrambillaA, et al., 2019. Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression. Nat Commun, 10:5460.

[74]MoralesJC, KoolET, 1999. Minor groove interactions between polymerase and DNA: more essential to replication than Watson-Crick hydrogen bonds? J Am Chem Soc, 121(10):2323-2324.

[75]NaryshkinN, RevyakinA, KimY, et al., 2000. Structural organization of the RNA polymerase-promoter open complex. Cell, 101(6):601-611.

[76]OdellID, BarbourJE, MurphyDL, et al., 2011. Nucleosome disruption by DNA ligase III-XRCC1 promotes efficient base excision repair. Mol Cell Biol, 31(22):4623-4632.

[77]OdellID, WallaceSS, PedersonDS, 2013. Rules of engagement for base excision repair in chromatin. J Cell Physiol, 228(2):258-266.

[78]OlmonED, DelaneyS, 2017. Differential ability of five DNA glycosylases to recognize and repair damage on nucleosomal DNA. ACS Chem Biol, 12(3):692-701.

[79]Pil啪ysT, MarcinkowskiM, KukwaW, et al., 2019. ALKBH overexpression in head and neck cancer: potential target for novel anticancer therapy. Sci Rep, 9:13249.

[80]PoltoratskyV, HortonJK, PrasadR, et al., 2005. REV1 mediated mutagenesis in base excision repair deficient mouse fibroblast. DNA Repair (Amst), 4(10):1182-1188.

[81]PrasadR, LiuY, DeterdingLJ, et al., 2007. HMGB1 is a cofactor in mammalian base excision repair. Mol Cell, 27(5):829-841.

[82]QuirosS, RoosWP, KainaB, 2010. Processing of O⁶-methylguanine into DNA double-strand breaks requires two rounds of replication whereas apoptosis is also induced in subsequent cell cycles. Cell Cycle, 9(1):168-178.

[83]RingvollJ, NordstrandLM, V氓gb酶CB, et al., 2006. Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA. EMBO J, 25(10):2189-2198.

[84]RodriguezY, SmerdonMJ, 2013. The structural location of DNA lesions in nucleosome core particles determines accessibility by base excision repair enzymes. J Biol Chem, 288(19):13863-13875.

[85]RodriguezY, HowardMJ, CuneoMJ, et al., 2017. Unencumbered Pol 尾 lyase activity in nucleosome core particles. Nucleic Acids Res, 45(15):8901-8915.

[86]RoosW, BaumgartnerM, KainaB, 2004. Apoptosis triggered by DNA damage O⁶-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1. Oncogene, 23(2):359-367.

[87]RouleauM, PatelA, HendzelMJ, et al., 2010. PARP inhibition: PARP1 and beyond. Nat Rev Cancer, 10(4):293-301.

[88]RydbergB, LindahlT, 1982. Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-L-methionine is a potentially mutagenic reaction. EMBO J, 1(2):211-216.

[89]SafraM, Sas-ChenA, NirR, et al., 2017. The m¹A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature, 551(7679):251-255.

[90]SahaD, RabkinSD, MartuzaRL, 2020. Temozolomide antagonizes oncolytic immunovirotherapy in glioblastoma. J Immunother Cancer, 8(1):e000345.

[91]SeoKW, KleinerRE, 2020. YTHDF2 recognition of N¹-methyladenosine (m¹A)-modified RNA is associated with transcript destabilization. ACS Chem Biol, 15(1):132-139.

[92]ShibataA, KamadaN, MasumuraKI, et al., 2005. Parp-1 deficiency causes an increase of deletion mutations and insertions/rearrangements in vivo after treatment with an alkylating agent. Oncogene, 24(8):1328-1337.

[93]ShrivastavN, LiD, EssigmannJM, 2010. Chemical biology of mutagenesis and DNA repair: cellular responses to DNA alkylation. Carcinogenesis, 31(1):59-70.

[94]SobolRW, HortonJK, K眉hnR, et al., 1996. Requirement of mammalian DNA polymerase-尾 in base-excision repair. Nature, 379(6561):183-186.

[95]SobolRW, PrasadR, EvenskiA, et al., 2000. The lyase activity of the DNA repair protein 尾-polymerase protects from DNA-damage-induced cytotoxicity. Nature, 405(6788):807-810.

[96]SollJM, SobolRW, MosammaparastN, 2017. Regulation of DNA alkylation damage repair: lessons and therapeutic opportunities. Trends Biochem Sci, 42(3):206-218.

[97]SollJM, BricknerJR, MudgeMC, et al., 2018. RNA ligase-like domain in activating signal cointegrator 1 complex subunit 1 (ASCC1) regulates ASCC complex function during alkylation damage. J Biol Chem, 293(35):13524-13533.

[98]SossouM, Flohr-BeckhausC, SchulzI, et al., 2005. APE1 overexpression in XRCC1-deficient cells complements the defective repair of oxidative single strand breaks but increases genomic instability. Nucleic Acids Res, 33(1):298-306.

[99]StarcevicD, DalalS, SweasyJB, 2004. Is there a link between DNA polymerase 尾 and cancer? Cell Cycle, 3(8):996-999.

[100]StefanssonOA, HermanowiczS, van der HorstJ, et al., 2017. CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer. BMC Cancer, 17:469.

[101]Str枚belT, MadlenerS, TunaS, et al., 2017. Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma. Sci Rep, 7:9674.

[102]SunGH, ZhaoLJ, ZhongRG, et al., 2018. The specific role of O⁶-methylguanine-DNA methyltransferase inhibitors in cancer chemotherapy. Future Med Chem, 10(16):1971-1996.

[103]SvilarD, GoellnerEM, AlmeidaKH, et al., 2011. Base excision repair and lesion-dependent subpathways for repair of oxidative DNA damage. Antioxid Redox Signal, 14(12):2491-2507.

[104]TasakiM, ShimadaK, KimuraH, et al., 2011. ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small-cell lung cancer. Br J Cancer, 104(4):700-706.

[105]TavernaP, LiuLL, HwangHS, et al., 2001. Methoxyamine potentiates DNA single strand breaks and double strand breaks induced by temozolomide in colon cancer cells. Mutat Res, 485(4):269-281.

[106]TranTQ, Ishak GabraMB, LowmanXH, et al., 2017. Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes. PLoS Biol, 15(11):e2002810.

[107]TsuzukiT, KawateH, IwakumaT, 1998. Study on carcinogenesis and mutation suppression: repair of alkylation DNA damage and suppression of tumors. Fukuoka Igaku Zasshi, 89(1):1-10.

[108]UedaY, OoshioI, FusamaeY, et al., 2017. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells. Sci Rep, 7:42271.

[109]WangP, WuJ, MaSH, et al., 2015. Oncometabolite D-2-hydroxyglutarate inhibits ALKBH DNA repair enzymes and sensitizes IDH mutant cells to alkylating agents. Cell Rep, 13(11):2353-2361.

[110]WangX, LuZK, GomezA, et al., 2014. N⁶-methyladenosine-dependent regulation of messenger RNA stability. Nature, 505(7481):117-120.

[111]WarrenJJ, ForsbergLJ, BeeseLS, 2006. The structural basis for the mutagenicity of O⁶-methyl-guanine lesions. Proc Natl Acad Sci USA, 103(52):19701-19706.

[112]WatanabeS, IchimuraT, FujitaN, et al., 2003. Methylated DNA-binding domain 1 and methylpurine-DNA glycosylase link transcriptional repression and DNA repair in chromatin. Proc Natl Acad Sci USA, 100(22):12859-12864.

[113]WestdorpH, FennemannFL, WerenRDA, et al., 2016. Opportunities for immunotherapy in microsatellite instable colorectal cancer. Cancer Immunol Immunother, 65(10):1249-1259.

[114]XieCR, ShengHS, ZhangN, et al., 2016. Association of MSH6 mutation with glioma susceptibility, drug resistance and progression. Mol Clin Oncol, 5(2):236-240.

[115]YangGZ, SchererSJ, ShellSS, et al., 2004. Dominant effects of an Msh6 missense mutation on DNA repair and cancer susceptibility. Cancer Cell, 6(2):139-150.

[116]YorkSJ, ModrichP, 2006. Mismatch repair-dependent iterative excision at irreparable O⁶-methylguanine lesions in human nuclear extracts. J Biol Chem, 281(32):22674-22683.

[117]YoshiokaKI, YoshiokaY, HsiehP, 2006. ATR kinase activation mediated by MutS伪 and MutL伪 in response to cytotoxic O⁶-methylguanine adducts. Mol Cell, 22(4):501-510.

[118]YuanCL, HeF, YeJZ, et al., 2017. APE1 overexpression is associated with poor survival in patients with solid tumors: a meta-analysis. Oncotarget, 8(35):59720-59728.

[119]ZhangC, JiaGF, 2018. Reversible RNA modification N¹-methyladenosine (m¹A) in mRNA and tRNA. Genomics Proteomics Bioinformatics, 16(3):155-161.

[120]ZhaoBS, RoundtreeIA, HeC, 2017. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol, 18(1):31-42.