表观遗传调控:基于染色质环境的DNA双链断裂修复
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摘要
DNA双链断裂(DNA double-strand breaks, DSBs)是威胁基因组完整性和细胞存活的最有害的DNA损伤类型。同源重组(homologous recombination,HR)和非同源末端连接(non-homologous end joining,NHEJ)是修复DNA双链断裂的两种主要途径。DSB修复涉及到损伤部位修复蛋白的募集和染色质结构的改变。在DNA双链断裂诱导下,染色质结构的动态变化在时间和空间上受到严格调控,进而对DNA双链断裂修复过程进行精细调节。特定的染色质修饰形成利于修复的染色质状态,有助于DNA双链断裂修复机器的招募、修复途径的选择和DNA损伤检查点的活化;其中修复途径的选择对于基因组稳定性至关重要。修复不当或失败可导致基因组不稳定性,甚至促进肿瘤的发生。本文综述了染色质结构和染色质修饰的动态变化在DSB修复中的重要作用。此外,文章还总结了在癌症治疗中靶向关键染色质调控因子在基因组稳定性维持、肿瘤发生发展以及潜在临床应用价值等方面的进展。
DNA double-strand breaks(DSBs) is the most deleterious DNA lesion that threatens genomic integrity and cell survival. Homologous recombination(HR) and non-homologous end joining(NHEJ) are the two major repair pathways. The repair of DSBs involves both concentration of DNA repair proteins at the site of damage and alterations of chromatin structure. Dynamic changes of chromatin architecture surrounding the DSBs are spatially and temporally regulated, so as to elaborately regulate DSB repair. Specific chromatin modifications develop a repair permissive chromatin state, which directly contributes to the access and assembly of DSB repair machinery, channels repair pathway choice and controls DNA damage checkpoints. Notably, repair pathway choice is critical to genome stability. Inappropriate repair or repair failure will lead to genome instability and even contribute to tumorigenesis. In this review, we summarize the important roles of chromatin structure and dynamic changes of chromatin modifications in DSB repair. Also, we highlight the concept of targeting chromatin regulators in response to genotoxic stress for cancer treatment, and how this can provide significant opportunities for DNA damage-based therapies in the future.
DNA double-strand breaks(DSBs) is the most deleterious DNA lesion that threatens genomic integrity and cell survival. Homologous recombination(HR) and non-homologous end joining(NHEJ) are the two major repair pathways. The repair of DSBs involves both concentration of DNA repair proteins at the site of damage and alterations of chromatin structure. Dynamic changes of chromatin architecture surrounding the DSBs are spatially and temporally regulated, so as to elaborately regulate DSB repair. Specific chromatin modifications develop a repair permissive chromatin state, which directly contributes to the access and assembly of DSB repair machinery, channels repair pathway choice and controls DNA damage checkpoints. Notably, repair pathway choice is critical to genome stability. Inappropriate repair or repair failure will lead to genome instability and even contribute to tumorigenesis. In this review, we summarize the important roles of chromatin structure and dynamic changes of chromatin modifications in DSB repair. Also, we highlight the concept of targeting chromatin regulators in response to genotoxic stress for cancer treatment, and how this can provide significant opportunities for DNA damage-based therapies in the future.
引文
[1] Zhu P,Li G.Structural insights of nucleosome and the 30-nm chromatin fiber[J].Curr Opin Struct Biol,2016,36:106-115
[2] Dekker J,Mirny L.The 3D genome as moderator of chromosomal communication[J].Cell,2016,164(6):1110-1121
[3] Mladenov E,Magin S,Soni A,et al.DNA double-strand-break repair in higher eukaryotes and its role in genomic instability and cancer:Cell cycle and proliferation-dependent regulation [J].Semin Cancer Biol,2016,37-38:51-64
[4] Lee CS,Wang RF,Chang HH,et al.Chromosome position determines the success of double- strand break repair[J].Proc Natl Acad Sci U S A,2016,113(2):E146-E154
[5] Agmon N,Liefshitz B,Zimmer C,et al.Effect of nuclear architecture on the efficiency of double-strand break repair[J].Nat Cell Biol,2013,15(6):694-699
[6] Clouaire T,Legube G.DNA double strand break repair pathway choice:a chromatin based decision?[J].Nucleus,2015,6(2):107-113
[7] Kalousi A,Soutoglou E.Nuclear compartmentalization of DNA repair[J].Curr Opin Genet Dev,2016,37:148-157
[8] Blackford AN,Jackson SP.ATM,ATR,and DNA-PK:The trinity at the heart of the DNA damage response[J].Mol Cell,2017,66(6):801-817
[9] O’Connor MJ.Targeting the DNA damage response in cancer[J].Mol Cell,2015,60(4):547-560
[10] Watanabe S,Watanabe K,Akimov V,et al.JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks[J].Nat Struct Mol Biol,2013,20(12):1425-1433
[11] Wang Q,Ma S,Song N,et al.Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis[J].J Clin Invest,2016,126(6):2205-2220
[12] Tang J,Cho NW,Cui G,et al.Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination[J].Nat Struct Mol Biol,2013,20(3):317-325
[13] Pfister SX,Ahrabi S,Zalmas LP,et al.SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability[J].Cell Rep,2014,7(6):2006-2018
[14] Feinberg AP,Koldobskiy MA,G?nd?r A.Epigenetic modulators,modifiers and mediators in cancer aetiology and progression[J].Nat Rev Genet,2016,17(5):284-299
[15] Caron P,Aymard F,Iacovoni JS,et al.Cohesin protects genes against γH2AX induced by DNA double-strand breaks[J].PLoS Genet,2012,8(1):e1002460
[16] Aymard F,Legube G.A TAD closer to ATM[J].Mol Cell Oncol,2016,3(3):e1134411
[17] Savic VB,Yin NL,Maas NL,et al.Formation of dynamic γ-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin[J].Mol Cell,2009,34(3):298-310
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[19] Uhlmann F.SMC complexes:from DNA to chromosomes[J].Nat Rev Mol Cell Biol,2016,17(7):399-412
[20] Gelot C,Guirouilh-Barbat J,Le Guen T,et al.The cohesin complex prevents the end joining of distant DNA double-strand ends[J].Mol Cell,2016,61(1):15-26
[21] Altmeyer M,Neelsen KJ,Teloni F,et al.Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)[J].Nat Commun,2015,6:8088
[22] Kruhlak MJ,Celeste A,Dellaire G,et al.Changes in chromatin structure and mobility in living cells at sites of DNA double-strand breaks[J].J Cell Biol,2006,172(6):823-834
[23] Smeenk G,Wiegant WW,Marteijn JA,et al.Poly(ADP-ribosyl)ation links the chromatin remodeler SMARCA5/SNF2H to RNF168-dependent DNA damage signaling[J].J Cell Sci,2013,126(4):889-903
[24] Strickfaden H,McDonald D,Kruhlak MJ,et al.Poly(ADP-ribosyl)ation-dependent transient chromatin decondensation and histone displacement following laser microirradiation[J].J Biol Chem,2016,291(4):1789-1802
[25] Burgess RC,Burman B,Kruhlak MJ,et al.Activation of DNA damage response signaling by condensed chromatin[J].Cell Rep,2014,9(5):1703-1717
[26] Lema?tre C,Soutoglou E.Double strand break (DSB) repair in heterochromatin and heterochromatin proteins in DSB repair[J].DNA Repair(Amst),2014,19:163-168
[27] Downs JA,Lowndes NF,Jackson SP.A role for Saccharomyces cerevisiae histone H2A in DNA repair[J].Nature,2000,408(6815):1001-1004
[28] Ziv Y,Bielopolski D,Galanty Y,et al.Chromatin relaxation in response to DNA double- strand breaks is modulated by a novel ATM-and KAP-1 dependent pathway[J].Nat Cell Biol,2006,8(8):870-876
[29] Lee HS,Park JH,Kim SJ,et al.A cooperative activation loop among SWI/SNF,gamma- H2AX and H3 acetylation for DNA double-strand break repair[J].EMBO J,2010,29(8):1434-1445
[30] Toiber D,Erdel F,Bouazoune K,et al.SIRT6 recruits SNF2H to DNA break sites,preventing genomic instability through chromatin remodeling[J].Mol Cell,2013,51(4):454-468
[31] Bennett G,Peterson CL.SWI/SNF recruitment to a DNA double-strand break by the NuA4 and Gcn5 histone acetyltransferases[J].DNA Repair(Amst),2015,30:38-45
[32] Schwertman P,Bekker-Jensen S,Mailand N.Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers[J].Nat Rev Mol Cell Biol,2016,17(6):379-394
[33] Li Z,Li Y,Tang M,et al.Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair[J].Cell Res,2018,28(7):756-770
[34] Clouaire T,Rocher V,Lashgari A,et al.Comprehensive mapping of histone modifications at DNA double-strand breaks deciphers repair pathway chromatin signatures[J].Mol Cell,2018,72(2):250-262.e6
[35] Her J,Bunting SF.How cells ensure correct repair of DNA double-strand breaks[J].J Biol Chem,2018,293(27):10502-10511
[36] Ghezraoui H,Oliveira C,Becker JR,et al.53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ[J].Nature,2018,560(7716):122-127
[37] Mirman Z,Lottersberger F,Takai H,et al.53BP1-RIF1-shieldin counteracts DSB resection through CST- and Pol alpha-dependent fill-in[J].Nature,2018,560(7716):112-116
[38] Gupta R,Somyajit K,Narita T,et al.DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity[J].Cell,2018,173(4):972-988
[39] Botuyan MV,Lee J,Ward IM,et al.Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair[J].Cell,2006,127(7):1361-1373
[40] Fradet-Turcotte A,Canny MD,Escribano-Diaz C,et al.53BP1 is a reader of the DNA- damage-induced H2A Lys 15 ubiquitin mark[J].Nature,2013,499(7456):50-54
[41] Pellegrino S,Michelena J,Teloni F,et al.replication-coupled dilution of H4K20me2 guides 53BP1 to pre-replicative chromatin[J].Cell Rep,2017,19(9):1819-1831
[42] Acs K,Luijsterburg MS,Ackermann L,et al.The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks[J].Nat Struct Mol Biol,2011,18(12):1345-1350
[43] Mallette FA,Mattiroli F,Cui G,et al.RNF8-and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites[J].EMBO J,2012,31(8):1865-1878
[44] Drane P,Brault ME,Cui G,et al.TIRR regulates 53BP1 by masking its histone methyl- lysine binding function[J].Nature,2017,543(7644):211-216
[45] Jacquet K,Fradet-Turcotte A,Avvakumov N,et al.The TIP60 complex regulates bivalent chromatin recognition by 53BP1 through direct H4K20me binding and H2AK15 acetylation[J].Mol Cell,2016,62(3):409-421
[46] Hu Q,Botuyan MV,Cui G,et al.Mechanisms of ubiquitin-nucleosome recognition and regulation of 53BP1 chromatin recruitment by RNF168/169 and RAD18[J].Mol Cell,2017,66(4):473-487
[47] Guo X,Bai Y,Zhao M,et al.Acetylation of 53BP1 dictates the DNA double strand break repair pathway[J].Nucleic Acids Res,2018,46(2):689-703
[48] Lee DH,Acharya SS,Kwon M,et al.Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks[J].Mol Cell,2014,54(3):512-525
[49] Aymard F,Bugler B,Schmidt CK,et al.Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks[J].Nat Struct Mol Biol,2014,21(4):366-374
[50] Carvalho S,Vitor AC,Sridhara SC,et al.SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint[J].Elife,2014,3:e02482
[51] Daugaard M,Baude A,Fugger K,et al.LEDGF (p75) promotes DNA-end resection and homologous recombination[J].Nat Struct Mol Biol,2012,19(8):803-810
[52] Lord CJ,Ashworth A.PARP inhibitors:Synthetic lethality in the clinic[J].Science,2017,355(6330):1152-1158
[53] Seeber A,Gasser SM.Chromatin organization and dynamics in double-strand break repair[J].Curr Opin Genet Dev,2017,43:9-16
[54] Price BD,D’Andrea AD.Chromatin remodeling at DNA double-strand breaks[J].Cell,2013,152(6):1344-1354
[55] Weber AM,Ryan AJ.ATM and ATR as therapeutic targets in cancer[J].Pharmacol Ther,2015,149:124-138
[56] Helleday T.The underlying mechanism for the PARP and BRCA synthetic lethality:Clearing up the misunderstandings[J].Mol Oncol,2011,5(4):387-393
[57] Bryant HE,Schultz N,Thomas HD,et al.Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase[J].Nature,2005,434(7035):913-917
[58] Ceccaldi R,Rondinelli B,D’Andrea AD.Repair pathway choices and consequences at the double-strand break[J].Trends Cell Biol,2016,26(1):52-64
[59] Ceccaldi R,Liu JC,Amunugama R,et al.Homologous-recombination-deficient tumours are dependent on Pol theta-mediated repair[J].Nature,2015,518(7538):258-262
[60] Ying S,Hamdy FC,Helleday T.Mre11-Dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1[J].Cancer Res,2012,72(11):2814-2821
[61] Schlacher K,Christ N,Siaud N,et al.Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11[J].Cell,2011,145(4):529-542
[62] Williamson CT,Miller R,Pemberton HN,et al.ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A[J].Nat Commun,2016,7:13837
[63] Shen J,Peng Y,Wei L,et al.ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors[J].Cancer Discov,2015,5(7):752-767
[64] Li X,Baek G,Ramanand SG,et al.BRD4 promotes DNA repair and mediates the formation of TMPRSS2-ERG gene rearrangements in prostate cancer[J].Cell Rep,2018,22(3):796-808
[65] Su D,Ma S,Shan L,et al.Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis[J].J Clin Invest,2018,128(10):4280-4296
[66] Zhao Y,Garcia BA.Comprehensive catalog of currently documented histone modifications [J].Cold Spring Harb Perspect Biol,2015,7(9):a025064
[2] Dekker J,Mirny L.The 3D genome as moderator of chromosomal communication[J].Cell,2016,164(6):1110-1121
[3] Mladenov E,Magin S,Soni A,et al.DNA double-strand-break repair in higher eukaryotes and its role in genomic instability and cancer:Cell cycle and proliferation-dependent regulation [J].Semin Cancer Biol,2016,37-38:51-64
[4] Lee CS,Wang RF,Chang HH,et al.Chromosome position determines the success of double- strand break repair[J].Proc Natl Acad Sci U S A,2016,113(2):E146-E154
[5] Agmon N,Liefshitz B,Zimmer C,et al.Effect of nuclear architecture on the efficiency of double-strand break repair[J].Nat Cell Biol,2013,15(6):694-699
[6] Clouaire T,Legube G.DNA double strand break repair pathway choice:a chromatin based decision?[J].Nucleus,2015,6(2):107-113
[7] Kalousi A,Soutoglou E.Nuclear compartmentalization of DNA repair[J].Curr Opin Genet Dev,2016,37:148-157
[8] Blackford AN,Jackson SP.ATM,ATR,and DNA-PK:The trinity at the heart of the DNA damage response[J].Mol Cell,2017,66(6):801-817
[9] O’Connor MJ.Targeting the DNA damage response in cancer[J].Mol Cell,2015,60(4):547-560
[10] Watanabe S,Watanabe K,Akimov V,et al.JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks[J].Nat Struct Mol Biol,2013,20(12):1425-1433
[11] Wang Q,Ma S,Song N,et al.Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis[J].J Clin Invest,2016,126(6):2205-2220
[12] Tang J,Cho NW,Cui G,et al.Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination[J].Nat Struct Mol Biol,2013,20(3):317-325
[13] Pfister SX,Ahrabi S,Zalmas LP,et al.SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability[J].Cell Rep,2014,7(6):2006-2018
[14] Feinberg AP,Koldobskiy MA,G?nd?r A.Epigenetic modulators,modifiers and mediators in cancer aetiology and progression[J].Nat Rev Genet,2016,17(5):284-299
[15] Caron P,Aymard F,Iacovoni JS,et al.Cohesin protects genes against γH2AX induced by DNA double-strand breaks[J].PLoS Genet,2012,8(1):e1002460
[16] Aymard F,Legube G.A TAD closer to ATM[J].Mol Cell Oncol,2016,3(3):e1134411
[17] Savic VB,Yin NL,Maas NL,et al.Formation of dynamic γ-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin[J].Mol Cell,2009,34(3):298-310
[18] Zhang Y,Heermann DW.DNA double-strand breaks:Linking gene expression to chromosome morphology and mobility[J].Chromosoma,2014,123(1-2):103-115
[19] Uhlmann F.SMC complexes:from DNA to chromosomes[J].Nat Rev Mol Cell Biol,2016,17(7):399-412
[20] Gelot C,Guirouilh-Barbat J,Le Guen T,et al.The cohesin complex prevents the end joining of distant DNA double-strand ends[J].Mol Cell,2016,61(1):15-26
[21] Altmeyer M,Neelsen KJ,Teloni F,et al.Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)[J].Nat Commun,2015,6:8088
[22] Kruhlak MJ,Celeste A,Dellaire G,et al.Changes in chromatin structure and mobility in living cells at sites of DNA double-strand breaks[J].J Cell Biol,2006,172(6):823-834
[23] Smeenk G,Wiegant WW,Marteijn JA,et al.Poly(ADP-ribosyl)ation links the chromatin remodeler SMARCA5/SNF2H to RNF168-dependent DNA damage signaling[J].J Cell Sci,2013,126(4):889-903
[24] Strickfaden H,McDonald D,Kruhlak MJ,et al.Poly(ADP-ribosyl)ation-dependent transient chromatin decondensation and histone displacement following laser microirradiation[J].J Biol Chem,2016,291(4):1789-1802
[25] Burgess RC,Burman B,Kruhlak MJ,et al.Activation of DNA damage response signaling by condensed chromatin[J].Cell Rep,2014,9(5):1703-1717
[26] Lema?tre C,Soutoglou E.Double strand break (DSB) repair in heterochromatin and heterochromatin proteins in DSB repair[J].DNA Repair(Amst),2014,19:163-168
[27] Downs JA,Lowndes NF,Jackson SP.A role for Saccharomyces cerevisiae histone H2A in DNA repair[J].Nature,2000,408(6815):1001-1004
[28] Ziv Y,Bielopolski D,Galanty Y,et al.Chromatin relaxation in response to DNA double- strand breaks is modulated by a novel ATM-and KAP-1 dependent pathway[J].Nat Cell Biol,2006,8(8):870-876
[29] Lee HS,Park JH,Kim SJ,et al.A cooperative activation loop among SWI/SNF,gamma- H2AX and H3 acetylation for DNA double-strand break repair[J].EMBO J,2010,29(8):1434-1445
[30] Toiber D,Erdel F,Bouazoune K,et al.SIRT6 recruits SNF2H to DNA break sites,preventing genomic instability through chromatin remodeling[J].Mol Cell,2013,51(4):454-468
[31] Bennett G,Peterson CL.SWI/SNF recruitment to a DNA double-strand break by the NuA4 and Gcn5 histone acetyltransferases[J].DNA Repair(Amst),2015,30:38-45
[32] Schwertman P,Bekker-Jensen S,Mailand N.Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers[J].Nat Rev Mol Cell Biol,2016,17(6):379-394
[33] Li Z,Li Y,Tang M,et al.Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair[J].Cell Res,2018,28(7):756-770
[34] Clouaire T,Rocher V,Lashgari A,et al.Comprehensive mapping of histone modifications at DNA double-strand breaks deciphers repair pathway chromatin signatures[J].Mol Cell,2018,72(2):250-262.e6
[35] Her J,Bunting SF.How cells ensure correct repair of DNA double-strand breaks[J].J Biol Chem,2018,293(27):10502-10511
[36] Ghezraoui H,Oliveira C,Becker JR,et al.53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ[J].Nature,2018,560(7716):122-127
[37] Mirman Z,Lottersberger F,Takai H,et al.53BP1-RIF1-shieldin counteracts DSB resection through CST- and Pol alpha-dependent fill-in[J].Nature,2018,560(7716):112-116
[38] Gupta R,Somyajit K,Narita T,et al.DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity[J].Cell,2018,173(4):972-988
[39] Botuyan MV,Lee J,Ward IM,et al.Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair[J].Cell,2006,127(7):1361-1373
[40] Fradet-Turcotte A,Canny MD,Escribano-Diaz C,et al.53BP1 is a reader of the DNA- damage-induced H2A Lys 15 ubiquitin mark[J].Nature,2013,499(7456):50-54
[41] Pellegrino S,Michelena J,Teloni F,et al.replication-coupled dilution of H4K20me2 guides 53BP1 to pre-replicative chromatin[J].Cell Rep,2017,19(9):1819-1831
[42] Acs K,Luijsterburg MS,Ackermann L,et al.The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks[J].Nat Struct Mol Biol,2011,18(12):1345-1350
[43] Mallette FA,Mattiroli F,Cui G,et al.RNF8-and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites[J].EMBO J,2012,31(8):1865-1878
[44] Drane P,Brault ME,Cui G,et al.TIRR regulates 53BP1 by masking its histone methyl- lysine binding function[J].Nature,2017,543(7644):211-216
[45] Jacquet K,Fradet-Turcotte A,Avvakumov N,et al.The TIP60 complex regulates bivalent chromatin recognition by 53BP1 through direct H4K20me binding and H2AK15 acetylation[J].Mol Cell,2016,62(3):409-421
[46] Hu Q,Botuyan MV,Cui G,et al.Mechanisms of ubiquitin-nucleosome recognition and regulation of 53BP1 chromatin recruitment by RNF168/169 and RAD18[J].Mol Cell,2017,66(4):473-487
[47] Guo X,Bai Y,Zhao M,et al.Acetylation of 53BP1 dictates the DNA double strand break repair pathway[J].Nucleic Acids Res,2018,46(2):689-703
[48] Lee DH,Acharya SS,Kwon M,et al.Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks[J].Mol Cell,2014,54(3):512-525
[49] Aymard F,Bugler B,Schmidt CK,et al.Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks[J].Nat Struct Mol Biol,2014,21(4):366-374
[50] Carvalho S,Vitor AC,Sridhara SC,et al.SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint[J].Elife,2014,3:e02482
[51] Daugaard M,Baude A,Fugger K,et al.LEDGF (p75) promotes DNA-end resection and homologous recombination[J].Nat Struct Mol Biol,2012,19(8):803-810
[52] Lord CJ,Ashworth A.PARP inhibitors:Synthetic lethality in the clinic[J].Science,2017,355(6330):1152-1158
[53] Seeber A,Gasser SM.Chromatin organization and dynamics in double-strand break repair[J].Curr Opin Genet Dev,2017,43:9-16
[54] Price BD,D’Andrea AD.Chromatin remodeling at DNA double-strand breaks[J].Cell,2013,152(6):1344-1354
[55] Weber AM,Ryan AJ.ATM and ATR as therapeutic targets in cancer[J].Pharmacol Ther,2015,149:124-138
[56] Helleday T.The underlying mechanism for the PARP and BRCA synthetic lethality:Clearing up the misunderstandings[J].Mol Oncol,2011,5(4):387-393
[57] Bryant HE,Schultz N,Thomas HD,et al.Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase[J].Nature,2005,434(7035):913-917
[58] Ceccaldi R,Rondinelli B,D’Andrea AD.Repair pathway choices and consequences at the double-strand break[J].Trends Cell Biol,2016,26(1):52-64
[59] Ceccaldi R,Liu JC,Amunugama R,et al.Homologous-recombination-deficient tumours are dependent on Pol theta-mediated repair[J].Nature,2015,518(7538):258-262
[60] Ying S,Hamdy FC,Helleday T.Mre11-Dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1[J].Cancer Res,2012,72(11):2814-2821
[61] Schlacher K,Christ N,Siaud N,et al.Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11[J].Cell,2011,145(4):529-542
[62] Williamson CT,Miller R,Pemberton HN,et al.ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A[J].Nat Commun,2016,7:13837
[63] Shen J,Peng Y,Wei L,et al.ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors[J].Cancer Discov,2015,5(7):752-767
[64] Li X,Baek G,Ramanand SG,et al.BRD4 promotes DNA repair and mediates the formation of TMPRSS2-ERG gene rearrangements in prostate cancer[J].Cell Rep,2018,22(3):796-808
[65] Su D,Ma S,Shan L,et al.Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis[J].J Clin Invest,2018,128(10):4280-4296
[66] Zhao Y,Garcia BA.Comprehensive catalog of currently documented histone modifications [J].Cold Spring Harb Perspect Biol,2015,7(9):a025064