Abstract
Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break (DSB) signaling. P53-binding protein 1 (53BP1) plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining (NHEJ)-mediated DSB repair pathway that rejoins DSB ends. New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination (HR) signaling. This review focuses on the up- and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair, which in turn promotes the sensitivity of poly(ADP-ribose) polymerase inhibitor (PARPi) in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies.
概要
DNA双链断裂(DSB)信号转导的关键作用是维持细胞的稳态和基因组的完整性。P53结合蛋白1(53BP1)在DSB修复信号选择中起到了关键的调节作用:53BP1能够促进DSB末端重新连接,从而促进非同源末端链接(NHEJ)介导的DSB修复途径。53BP1如何被招募到DNA损伤位点以及53BP1如何招募其DNA损伤修复效应子,从而促进NHEJ介导的DSB修复,并抑制同源重组(HR)信号传导?最新的研究对于这些问题有了进一步的阐述。这篇综述将着重于阐述53BP1蛋白是如何促进NHEJ介导的DSB修复途径以及其上下游通路蛋白调控,从而促进BRCA1缺陷型癌症细胞对多聚ADP-核糖聚合酶抑制剂(PARPi)的敏感性,最终为改善癌症治疗策略提供新的方向。
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08 April 2021
The typesetting format of the online version of the first issue (2021 22(01)) of Journal of Zhejiang University-SCIENCE B is different from that of the printed version (but all the text, figure and table contents in the article are correct). This is due to the new typesetting company adopted this year.
References
Abraham RT, 2002. Checkpoint signalling: focusing on 53BP1. Nat Cell Biol, 4(12):E277–E279. https://doi.org/10.1038/ncb1202-e277
Adams MM, Carpenter PB, 2006. Tying the loose ends together in DNA double strand break repair with 53BP1. Cell Div, 1:19. https://doi.org/10.1186/1747-1028-1-19
Anderson L, Henderson C, Adachi Y, 2001. Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Mol Cell Biol, 21(5):1719–1729. https://doi.org/10.1128/MCB.21.5.1719-1729.2001
Bekker-Jensen S, Mailand N, 2011. The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaks. FEBS Lett, 585(18):2914–2919. https://doi.org/10.1016/j.febslet.2011.05.056
Boersma V, Moatti N, Segura-Bayona S, et al., 2015. MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection. Nature, 521(7553): 537–540. https://doi.org/10.1038/nature14216
Bothmer A, Robbiani DF, di Virgilio M, et al., 2011. Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1. Mol Cell, 42(3): 319–329. https://doi.org/10.1016/j.molcel.2011.03.019
Botuyan MV, Lee J, Ward IM, et al., 2006. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell, 127(7): 1361–1373. https://doi.org/10.1016/j.cell.2006.10.043
Botuyan MV, Cui GF, Drané P, et al., 2018. Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein. Nat Struct Mol Biol, 25(7):591–600. https://doi.org/10.1038/s41594-018-0083-z
Bouwman P, Aly A, Escandell JM, et al., 2010. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol, 17(6):688–695. https://doi.org/10.1038/nsmb.1831
Bryant HE, Schultz N, Thomas HD, et al., 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature, 434(7035):913–917. https://doi.org/10.1038/nature03443
Bunting SF, Callen E, Wong N, et al., 2010. 53BP1 inhibits homologous recombination in BRCA1-deficient cells by blocking resection of DNA breaks. Cell, 141(2):243–254. https://doi.org/10.1016/j.cell.2010.03.012
Bunting SF, Callén E, Kozak ML, et al., 2012. Brca1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol Cell, 46(2): 125–135. https://doi.org/10.1016/j.molcel.2012.02.015
Callen E, Faryabi RB, Luckey M, et al., 2012. The DNA damage-and transcription-associated protein Paxip1 controls thymocyte development and emigration. Immunity, 37(6): 971–985. https://doi.org/10.1016/j.immuni.2012.10.007
Callen E, di Virgilio M, Kruhlak MJ, et al., 2013. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell, 153(6):1266–1280. https://doi.org/10.1016/j.cell.2013.05.023
Chapman JR, Sossick AJ, Boulton SJ, et al., 2012a. BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J Cell Sci, 125(Pt 15):3529–3534. https://doi.org/10.1242/jcs.105353
Chapman JR, Taylor MRG, Boulton SJ, 2012b. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell, 47(4):497–510. https://doi.org/10.1016/j.molcel.2012.07.029
Chapman JR, Barral P, Vannier JB, et al., 2013. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol Cell, 49(5):858–871. https://doi.org/10.1016/j.molcel.2013.01.002
Charier G, Couprie J, Alpha-Bazin B, et al., 2004. The Tudor tandem of 53BP1: a new structural motif involved in DNA and RG-rich peptide binding. Structure, 12(9): 1551–1562. https://doi.org/10.1016/j.str.2004.06.014
Cho YW, Hong T, Hong SH, et al., 2007. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4: methyltransferase complex. J Biol Chem, 282(28):20395–20406. https://doi.org/10.1074/jbc.M701574200
Dai YX, Zhang AL, Shan S, et al., 2018. Structural basis for recognition of 53BP1 tandem Tudor domain by TIRR. Nat Commun, 9:2123. https://doi.org/10.1038/s41467-018-04557-2
Dai YX, Zhang F, Wang LG, et al., 2020. Structural basis for shieldin complex subunit 3-mediated recruitment of the checkpoint protein REV7 during DNA double-strand break repair. J Biol Chem, 295(1):250–262. https://doi.org/10.1074/jbc.RA119.011464
Dev H, Chiang TWW, Lescale C, et al., 2018. Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat Cell Biol, 20(8):954–965. https://doi.org/10.1038/s41556-018-0140-1
di Virgilio M, Callen E, Yamane A, et al., 2013. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science, 339(6120):711–715. https://doi.org/10.1126/science.1230624
Doil C, Mailand N, Bekker-Jensen S, et al., 2009. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell, 136(3):435–446. https://doi.org/10.1016/j.cell.2008.12.041
Drané P, Brault ME, Cui GF, et al., 2017. TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature, 543(7644):211–216. https://doi.org/10.1038/nature21358
Escribano-Díaz C, Orthwein A, Fradet-Turcotte A, et al., 2013. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell, 49(5):872–883. https://doi.org/10.1016/j.molcel.2013.01.001
Farmer H, McCabe N, Lord CJ, et al., 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 434(7035):917–921. https://doi.org/10.1038/nature03445
Feng L, Fong KW, Wang JD, et al., 2013. RIF1 counteracts BRCA1-mediated end resection during DNA repair. J Biol Chem, 288(16):11135–11143. https://doi.org/10.1074/jbc.M113.457440
Fitzgerald JE, Grenon M, Lowndes NF, 2009. 53BP1: function and mechanisms of focal recruitment. Biochem Soc Trans, 37(Pt 4):897–904. https://doi.org/10.1042/BST0370897
Fradet-Turcotte A, Canny MD, Escribano-Díaz C, et al., 2013. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature, 499(7456):50–54. https://doi.org/10.1038/nature12318
Gatti M, Pinato S, Maspero E, et al., 2012. A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by RNF168 ubiquitin ligase. Cell Cycle, 11(13):2538–2544. https://doi.org/10.4161/cc.20919
Ghezraoui H, Oliveira C, Becker JR, et al., 2018. 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature, 560(7716):122–127. https://doi.org/10.1038/s41586-018-0362-1
Gong ZH, Cho YW, Kim JE, et al., 2009. Accumulation of Pax2 transactivation domain interaction protein (PTIP) at sites of DNA breaks via RNF8-dependent pathway is required for cell survival after DNA damage. J Biol Chem, 284(11):7284–7293. https://doi.org/10.1074/jbc.M809158200
Goodarzi AA, Jeggo PA, 2013. The repair and signaling responses to DNA double-strand breaks. Adv Genet, 82:1–45. https://doi.org/10.1016/B978-0-12-407676-1.00001-9
Guo X, Bai YT, Zhao MM, et al., 2018. Acetylation of 53BP1 dictates the DNA double strand break repair pathway. Nucleic Acids Res, 46(2):689–703. https://doi.org/10.1093/nar/gkx1208
Gupta R, Somyajit K, Narita T, et al., 2018. DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity. Cell, 173(4): 972–988.E923. https://doi.org/10.1016/j.cell.2018.03.050
Heyer WD, Ehmsen KT, Liu J, 2010. Regulation of homologous recombination in eukaryotes. Annu Rev Genet, 44: 113–139. https://doi.org/10.1146/annurev-genet-051710-150955
Huen MS, Grant R, Manke I, et al., 2007. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell, 131 (5):901–914. https://doi.org/10.1016/j.cell.2007.09.041
Huen MSY, Huang J, Leung JWC, et al., 2010. Regulation of chromatin architecture by the PWWP domain-containing DNA damage-responsive factor EXPAND1/MUM1. Mol Cell, 37(6):854–864. https://doi.org/10.1016/j.molcel.2009.12.040
Isono M, Niimi A, Oike T, et al., 2017. BRCA1 directs the repair pathway to homologous recombination by promoting 53BP1 dephosphorylation. Cell Rep, 18(2): 520–532. https://doi.org/10.1016/j.celrep.2016.12.042
Iwabuchi K, Basu BP, Kysela B, et al., 2003. Potential role for 53BP1 in DNA end-joining repair through direct interaction with DNA. J Biol Chem, 278(38):36487–36495. https://doi.org/10.1074/jbc.M304066200
Kolas NK, Chapman JR, Nakada S, et al., 2007. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science, 318(5856):1637–1640. https://doi.org/10.1126/science.1150034
Lieber MR, 2010. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem, 79:181–211. https://doi.org/10.1146/annurev.biochem.052308.093131
Lottersberger F, Bothmer A, Robbiani DF, et al., 2013. Role of 53BP1 oligomerization in regulating double-strand break repair. Proc Natl Acad Sci USA, 110(6):2146–2151. https://doi.org/10.1073/pnas.1222617110
Lukas J, Lukas C, Bartek J, 2011. More than just a focus: the chromatin response to DNA damage and its role in genome integrity maintenance. Nat Cell Biol, 13(10): 1161–1169. https://doi.org/10.1038/ncb2344
Ma YM, Pannicke U, Schwarz K, et al., 2002. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell, 108(6):781–794. https://doi.org/10.1016/s0092-8674(02)00671-2
Mailand N, Bekker-Jensen S, Faustrup H, et al., 2007. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell, 131(5):887–900. https://doi.org/10.1016/j.cell.2007.09.040
Manis JP, Morales JC, Xia ZF, et al., 2004. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat Immunol, 5(5):481–487. https://doi.org/10.1038/ni1067
Manke IA, Lowery DM, Nguyen A, et al., 2003. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science, 302(5645):636–639. https://doi.org/10.1126/science.1088877
Mattiroli F, Vissers JHA, van Dijk WJ, et al., 2012. RNF168 ubiquitinates K13–15 on H2A/H2AX to drive DNA damage signaling. Cell, 150(6):1182–1195. https://doi.org/10.1016/j.cell.2012.08.005
McLennan AG, 2006. The Nudix hydrolase superfamily. Cell Mol Life Sci, 63(2):123–143. https://doi.org/10.1007/s00018-005-5386-7
Mirman Z, Lottersberger F, Takai H, et al., 2018. 53BP1-RIF1-shieldin counteracts DSB resection through CST-and Polα-dependent fill-in. Nature, 560(7716):112–116. https://doi.org/10.1038/s41586-018-0324-7
Munoz IM, Jowsey PA, Toth R, et al., 2007. Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage. Nucleic Acids Res, 35(16):5312–5322. https://doi.org/10.1093/nar/gkm493
Noordermeer SM, Adam S, Setiaputra D, et al., 2018. The shieldin complex mediates 53BP1-dependent DNA repair. Nature, 560(7716):117–121. https://doi.org/10.1038/s41586-018-0340-7
Palazzo L, Thomas B, Jemth AS, et al., 2015. Processing of protein ADP-ribosylation by Nudix hydrolases. Biochem J, 468(2):293–301. https://doi.org/10.1042/BJ20141554
Panier S, Boulton SJ, 2014. Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol, 15(1):7–18. https://doi.org/10.1038/nrm3719
Polato F, Callen E, Wong N, et al., 2014. CtIP-mediated resection is essential for viability and can operate independently of BRCA1. J Exp Med, 211(6):1027–1036. https://doi.org/10.1084/jem.20131939
Rappold I, Iwabuchi K, Date T, et al., 2001. Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways. J Cell Biol, 153(3):613–620. https://doi.org/10.1083/jcb.153.3.613
Schultz LB, Chehab NH, Malikzay A, et al., 2000. P53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J Cell Biol, 151(7):1381–1390. https://doi.org/10.1083/jcb.151.7.1381
Setiaputra D, Durocher D, 2019. Shieldin—the protector of DNA ends. EMBO Rep, 20(5):e47560. https://doi.org/10.15252/embr.201847560
Stewart GS, Panier S, Townsend K, et al., 2009. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell, 136(3):420–434. https://doi.org/10.1016/j.cell.2008.12.042
Tomida J, Takata KI, Bhetawal S, et al., 2018. FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells. EMBO J, 37(12): e99543. https://doi.org/10.15252/embj.201899543
van Gent DC, 2009. Reaching out for the other end with p53-binding protein 1. Trends Biochem Sci, 34(5):226–229. https://doi.org/10.1016/j.tibs.2009.01.009
Wang B, Elledge SJ, 2007. Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci USA, 104(52):20759–20763. https://doi.org/10.1073/pnas.0710061104
Wang JD, Aroumougame A, Lobrich M, et al., 2014. PTIP associates with Artemis to dictate DNA repair pathway choice. Genes Dev, 28(24):2693–2698. https://doi.org/10.1101/gad.252478.114
Wang JX, Yuan ZL, Cui YQ, et al., 2018. Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR. Nat Commun, 9:2689. https://doi.org/10.1038/s41467-018-05174-9
Wang X, Takenaka K, Takeda S, 2010. PTIP promotes DNA double-strand break repair through homologous recombination. Genes Cells, 15(3):243–254. https://doi.org/10.1111/j.1365-2443.2009.01379.x
Ward IM, Reina-San-Martin B, Olaru A, et al., 2004. 53BP1 is required for class switch recombination. J Cell Biol, 165(4):459–464. https://doi.org/10.1083/jcb.200403021
Xu GT, Chapman JR, Brandsma I, et al., 2015. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature, 521(7553):541–544. https://doi.org/10.1038/nature14328
Yu XC, Chini CCS, He M, et al., 2003. The BRCT domain is a phospho-protein binding domain. Science, 302(5645): 639–642. https://doi.org/10.1126/science.1088753
Zhang AL, Peng B, Huang P, et al., 2017. The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. J Biol Chem, 292(16):6461–6467. https://doi.org/10.1074/jbc.M117.777474
Zhang F, Lou LH, Peng B, et al., 2020. Nudix hydrolase NUDT16 regulates 53BP1 protein by reversing 53BP1 ADP-ribosylation. Cancer Res, 80(5):999–1010. https://doi.org/10.1158/0008-5472.CAN-19-2205
Zimmermann M, Lottersberger F, Buonomo SB, et al., 2013. 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science, 339(6120):700–704. https://doi.org/10.1126/science.1231573
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Fan ZHANG wrote and edited the manuscript and drew the figures. Zihua GONG contributed to the revision of the manuscript and the figures. Both authors have read and approved the final manuscript and, therefore, take responsibility for the integrity and security of the manuscript.
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Fan ZHANG and Zihua GONG declare that they have no conflict of interest.
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Zhang, F., Gong, Z. Regulation of DNA double-strand break repair pathway choice: a new focus on 53BP1. J. Zhejiang Univ. Sci. B 22, 38–46 (2021). https://doi.org/10.1631/jzus.B2000306
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DOI: https://doi.org/10.1631/jzus.B2000306
Key words
- P53-binding protein 1 (53BP1)
- DNA double-strand break (DSB)
- Non-homologous end-joining (NHEJ)
- Homologous recombination (HR)
- Poly(ADP-ribose) polymerase inhibitor (PARPi)