Harnessing DOT1L and RAP80: unveiling new insights into BRCA1-mediated DNA repair for cancer therapy

Abstract

The article titled “DOT1L-mediated RAP80 methylation promotes BRCA1 recruitment to elicit DNA repair” was published in August 2024 in the Proceedings of the National Academy of Sciences (PNAS) by Tang et al. It presents significant advancements in understanding the mechanism of the DNA damage response (DDR), specifically in the context of BRCA1-mediated DNA repair. The authors discovered a novel role of DOT1L, a histone methyltransferase, in facilitating the recruitment of the BRCA1-A complex to DNA damage sites through the methylation of RAP80. This finding has profound implications for the development of new therapeutic strategies, particularly in overcoming resistance to radiotherapy in cancer treatment.

References

[1] CicciaA, ElledgeSJ. The DNA damage response: Making it safe to play with knives. Molecular Cell, 2010, 40: 179-204

[2] JacksonSP, BartekJ. The DNA-damage response in human biology and disease. Nature, 2009, 461: 1071-1078

[3] KimH, ChenJ, YuX. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science, 2007, 316: 1202-1205

[4] KimH, HuangJ, ChenJ. CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response. Nature Structural & Molecular Biology, 2007, 14: 710-715

[5] LiY, LuoK, YinY, WuC, DengM, LiL, ChenY, NowsheenS, LouZ, YuanJ. USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response. Nature Communications, 2017, 8: 15752

[6] LiuZ, WuJ, YuX. CCDC98 targets BRCA1 to DNA damage sites. Nature Structural & Molecular Biology, 2007, 14: 716-720

[7] LiuL, LinB, YinS, BallLE, DelaneyJR, LongDT, GanW. Arginine methylation of BRD4 by PRMT2/4 governs transcription and DNA repair. Science Advances, 2022, 8: eadd8928

[8] LordCJ, AshworthA. The DNA damage response and cancer therapy. Nature, 2012, 481: 287-294

[9] MattiroliF, VissersJH, van DijkWJ, IkpaP, CitterioE, VermeulenW, MarteijnJA, SixmaTK. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell, 2012, 150: 1182-1195

[10] RablJ, BunkerRD, SchenkAD, CavadiniS, GillME, AbdulrahmanW, Andres-PonsA, LuijsterburgMS, IbrahimAFM, BraniganE, et al. . Structural basis of BRCC36 function in DNA repair and Immune Regulation. Molecular Cell, 2019, 75: 483-497e489

[11] ScullyR, ChenJ, OchsRL, KeeganK, HoekstraM, FeunteunJ, LivingstonDM. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell, 1997, 90: 425-435

[12] SobhianB, ShaoG, LilliDR, CulhaneAC, MoreauLA, XiaB, LivingstonDM, GreenbergRA. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science, 2007, 316: 1198-1202

[13] Soo LeeN, ChungJ, KimH, Yun LeeHJ, JiS, SeoJH, HanYH, ChoiS, YunM, LeeM, et al. . TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage. Nature Communications, 2016, 7: 10463

[14] TangM, ChenG, TuB, HuZ, HuangY, DuFortCC, WanX, MaoZ, LiuY, ZhuWG, LuW. SMYD2 inhibition-mediated hypomethylation of Ku70 contributes to impaired nonhomologous end joining repair and antitumor immunity. Science Advances, 2023, 9: eade6624

[15] TangH, LuYF, ZengR, LiuC, ShuY, WuY, SuJ, DiL, QianJ, ZhangJ, et al. . DOT1L-mediated RAP80 methylation promotes BRCA1 recruitment to elicit DNA repair. Proc Natl Acad Sci U S A, 2024, 121: e2320804121

[16] TarsounasM, SungP. The antitumorigenic roles of BRCA1-BARD1 in DNA repair and replication. Nature Reviews Molecular Cell Biology, 2020, 21: 284-299

[17] WangB. BRCA1 tumor suppressor network: Focusing on its tail. Cell Biosci, 2012, 2: 6

[18] WangY, ZhangN, ZhangL, LiR, FuW, MaK, LiX, WangL, WangJ, ZhangH, et al. . Autophagy regulates chromatin ubiquitination in DNA damage response through elimination of SQSTM1/p62. Molecular Cell, 2016, 63: 34-48

[19] WuJ, HuenMS, LuLY, YeL, DouY, LjungmanM, ChenJ, YuX. Histone ubiquitination associates with BRCA1-dependent DNA damage response. Molecular and Cellular Biology, 2009, 29: 849-860

[20] XiaB, ShengQ, NakanishiK, OhashiA, WuJ, ChristN, LiuX, JasinM, CouchFJ, LivingstonDM. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Molecular Cell, 2006, 22: 719-729

Funding

National Natural Science Foundation of China(32090034)

Zhejiang Provincial Natural Science Foundation of China(2022XHSJJ001)

Pioneer and Leading Goose R&D Program of Zhejiang(2024SSYS0033)

Hangzhou City Leading Innovation and Entrepreneurship Team(TD2020004)