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.

DNA双链断裂修复途径选择的调控：53BP1蛋白最新研究关注

[1]AbrahamRT, 2002. Checkpoint signalling: focusing on 53BP1. Nat Cell Biol, 4(12):E277-E279.

[2]AdamsMM, CarpenterPB, 2006. Tying the loose ends together in DNA double strand break repair with 53BP1. Cell Div, 1:19.

[3]AndersonL, HendersonC, AdachiY, 2001. Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Mol Cell Biol, 21(5):1719-1729.

[4]Bekker-JensenS, MailandN, 2011. The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaks. FEBS Lett, 585(18):2914-2919.

[5]BoersmaV, MoattiN, Segura-BayonaS, et al., 2015. MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5' end resection. Nature, 521(7553):537-540.

[6]BothmerA, RobbianiDF, di VirgilioM, et al., 2011. Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1. Mol Cell, 42(3):319-329.

[7]BotuyanMV, LeeJ, WardIM, 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.

[8]BotuyanMV, CuiGF, Dran茅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.

[9]BouwmanP, AlyA, EscandellJM, 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.

[10]BryantHE, SchultzN, ThomasHD, et al., 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature, 434(7035):913-917.

[11]BuntingSF, CallenE, WongN, et al., 2010. 53BP1 inhibits homologous recombination in BRCA1-deficient cells by blocking resection of DNA breaks. Cell, 141(2):243-254.

[12]BuntingSF, Call茅nE, KozakML, et al., 2012. Brca1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol Cell, 46(2):125-135.

[13]CallenE, FaryabiRB, LuckeyM, et al., 2012. The DNA damage- and transcription-associated protein Paxip1 controls thymocyte development and emigration. Immunity, 37(6):971-985.

[14]CallenE, di VirgilioM, KruhlakMJ, et al., 2013. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell, 153(6):1266-1280.

[15]ChapmanJR, SossickAJ, BoultonSJ, 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.

[16]ChapmanJR, TaylorMRG, BoultonSJ, 2012b. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell, 47(4):497-510.

[17]ChapmanJR, BarralP, VannierJB, 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.

[18]CharierG, CouprieJ, Alpha-BazinB, 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.

[19]ChoYW, HongT, HongSH, et al., 2007. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4: methyltransferase complex. J Biol Chem, 282(28):20395-20406.

[20]DaiYX, ZhangAL, ShanS, et al., 2018. Structural basis for recognition of 53BP1 tandem Tudor domain by TIRR. Nat Commun, 9:2123.

[21]DaiYX, ZhangF, WangLG, 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.

[22]DevH, ChiangTWW, LescaleC, et al., 2018. Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat Cell Biol, 20(8):954-965.

[23]di VirgilioM, CallenE, YamaneA, et al., 2013. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science, 339(6120):711-715.

[24]DoilC, MailandN, Bekker-JensenS, et al., 2009. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell, 136(3):435-446.

[25]Dran茅P, BraultME, CuiGF, et al., 2017. TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature, 543(7644):211-216.

[26]Escribano-D铆azC, OrthweinA, Fradet-TurcotteA, 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.

[27]FarmerH, McCabeN, LordCJ, et al., 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 434(7035):917-921.

[28]FengL, FongKW, WangJD, et al., 2013. RIF1 counteracts BRCA1-mediated end resection during DNA repair. J Biol Chem, 288(16):11135-11143.

[29]FitzgeraldJE, GrenonM, LowndesNF, 2009. 53BP1: function and mechanisms of focal recruitment. Biochem Soc Trans, 37(Pt 4):897-904.

[30]Fradet-TurcotteA, CannyMD, Escribano-D铆azC, et al., 2013. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature, 499(7456):50-54.

[31]GattiM, PinatoS, MasperoE, 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.

[32]GhezraouiH, OliveiraC, BeckerJR, et al., 2018. 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature, 560(7716):122-127.

[33]GongZH, ChoYW, KimJE, 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.

[34]GoodarziAA, JeggoPA, 2013. The repair and signaling responses to DNA double-strand breaks. Adv Genet, 82:1-45.

[35]GuoX, BaiYT, ZhaoMM, et al., 2018. Acetylation of 53BP1 dictates the DNA double strand break repair pathway. Nucleic Acids Res, 46(2):689-703.

[36]GuptaR, SomyajitK, NaritaT, 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.

[37]HeyerWD, EhmsenKT, LiuJ, 2010. Regulation of homologous recombination in eukaryotes. Annu Rev Genet, 44:113-139.

[38]HuenMS, GrantR, MankeI, et al., 2007. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell, 131(5):901-914.

[39]HuenMSY, HuangJ, LeungJWC, et al., 2010. Regulation of chromatin architecture by the PWWP domain-containing DNA damage-responsive factor EXPAND1/MUM1. Mol Cell, 37(6):854-864.

[40]IsonoM, NiimiA, OikeT, et al., 2017. BRCA1 directs the repair pathway to homologous recombination by promoting 53BP1 dephosphorylation. Cell Rep, 18(2):520-532.

[41]IwabuchiK, BasuBP, KyselaB, et al., 2003. Potential role for 53BP1 in DNA end-joining repair through direct interaction with DNA. J Biol Chem, 278(38): 36487-36495.

[42]KolasNK, ChapmanJR, NakadaS, et al., 2007. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science, 318(5856):1637-1640.

[43]LieberMR, 2010. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem, 79:181-211.

[44]LottersbergerF, BothmerA, RobbianiDF, et al., 2013. Role of 53BP1 oligomerization in regulating double-strand break repair. Proc Natl Acad Sci USA, 110(6):2146-2151.

[45]LukasJ, LukasC, BartekJ, 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.

[46]MaYM, PannickeU, SchwarzK, 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.

[47]MailandN, Bekker-JensenS, FaustrupH, et al., 2007. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell, 131(5):887-900.

[48]ManisJP, MoralesJC, XiaZF, et al., 2004. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat Immunol, 5(5):481-487.

[49]MankeIA, LoweryDM, NguyenA, et al., 2003. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science, 302(5645):636-639.

[50]MattiroliF, VissersJHA, van DijkWJ, et al., 2012. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell, 150(6):1182-1195.

[51]McLennanAG, 2006. The Nudix hydrolase superfamily. Cell Mol Life Sci, 63(2):123-143.

[52]MirmanZ, LottersbergerF, TakaiH, et al., 2018. 53BP1-RIF1-shieldin counteracts DSB resection through CST- and Pol伪-dependent fill-in. Nature, 560(7716):112-116.

[53]MunozIM, JowseyPA, TothR, 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.

[54]NoordermeerSM, AdamS, SetiaputraD, et al., 2018. The shieldin complex mediates 53BP1-dependent DNA repair. Nature, 560(7716):117-121.

[55]PalazzoL, ThomasB, JemthAS, et al., 2015. Processing of protein ADP-ribosylation by Nudix hydrolases. Biochem J, 468(2):293-301.

[56]PanierS, BoultonSJ, 2014. Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol, 15(1):7-18.

[57]PolatoF, CallenE, WongN, et al., 2014. CtIP-mediated resection is essential for viability and can operate independently of BRCA1. J Exp Med, 211(6):1027-1036.

[58]RappoldI, IwabuchiK, DateT, et al., 2001. Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways. J Cell Biol, 153(3):613-620.

[59]SchultzLB, ChehabNH, MalikzayA, 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.

[60]SetiaputraD, DurocherD, 2019. Shieldin鈥攖he protector of DNA ends. EMBO Rep, 20(5):e47560.

[61]StewartGS, PanierS, TownsendK, et al., 2009. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell, 136(3):420-434.

[62]TomidaJ, TakataKI, BhetawalS, et al., 2018. FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells. EMBO J, 37(12):e99543.

[63]van GentDC, 2009. Reaching out for the other end with p53-binding protein 1. Trends Biochem Sci, 34(5):226-229.

[64]WangB, ElledgeSJ, 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.

[65]WangJD, AroumougameA, LobrichM, et al., 2014. PTIP associates with Artemis to dictate DNA repair pathway choice. Genes Dev, 28(24):2693-2698.

[66]WangJX, YuanZL, CuiYQ, et al., 2018. Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR. Nat Commun, 9:2689.

[67]WangX, TakenakaK, TakedaS, 2010. PTIP promotes DNA double-strand break repair through homologous recombination. Genes Cells, 15(3):243-254.

[68]WardIM, Reina-San-MartinB, OlaruA, et al., 2004. 53BP1 is required for class switch recombination. J Cell Biol, 165(4):459-464.

[69]XuGT, ChapmanJR, BrandsmaI, et al., 2015. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature, 521(7553):541-544.

[70]YuXC, ChiniCCS, HeM, et al., 2003. The BRCT domain is a phospho-protein binding domain. Science, 302(5645):639-642.

[71]ZhangAL, PengB, HuangP, 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.

[72]ZhangF, LouLH, PengB, et al., 2020. Nudix hydrolase NUDT16 regulates 53BP1 protein by reversing 53BP1 ADP-ribosylation. Cancer Res, 80(5):999-1010.

[73]ZimmermannM, LottersbergerF, BuonomoSB, et al., 2013. 53BP1 regulates DSB repair using Rif1 to control 5' end resection. Science, 339(6120):700-704.