A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice

被引：128

作者：

Zhang, Haoxing ^{[1
]}

Liu, Hailong ^{[2
]}

Chen, Yali ^{[2
]}

Yang, Xu ^{[2
]}

Wang, Panfei ^{[2
]}

Liu, Tongzheng ^{[3
]}

Deng, Min ^{[3
]}

Qin, Bo ^{[3
]}

Correia, Cristina ^{[3
]}

Lee, Seungbaek ^{[3
]}

Kim, Jungjin ^{[3
]}

Sparks, Melanie ^{[4
]}

Nair, Asha A. ^{[5
]}

Evans, Debra L. ^{[3
]}

Kalari, Krishna R. ^{[5
]}

Zhang, Pumin ^{[6
]}

Wang, Liewei ^{[7
]}

You, Zhongsheng ^{[4
]}

Kaufmann, Scott H. ^{[3
]}

Lou, Zhenkun ^{[2
,3
,7
]}

Pei, Huadong ^{[2
]}

机构：

[1] Southwest Univ, Sch Life Sci, Chongqing 400715, Peoples R China

[2] Beijing Inst Radiat Med, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing 100850, Peoples R China

[3] Mayo Clin, Div Oncol Res, Rochester, MN 55905 USA

[4] Washington Univ, Dept Cell Biol & Physiol, St Louis, MO 63130 USA

[5] Mayo Clin, BSI Genet & Bioinformat, Rochester, MN 55905 USA

[6] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA

[7] Mayo Clin, Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

中国国家自然科学基金;

关键词：

HOMOLOGOUS RECOMBINATION; END RESECTION; UHRF1; 53BP1; RECOGNITION; PROTEIN; RIF1; DOMAIN; PHD; PHOSPHORYLATION;

D O I：

10.1038/ncomms10201

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

BRCA1 is an important mediator of the DNA damage response, which promotes homologous recombination (HR) and antagonizes 53BP1-dependent non-homologous end joining in S/G2 phase. But how this is achieved remains unclear. Here, we report that the E3 ubiquitin ligase UHRF1 (Ubiquitin-like, with PHD and RING finger domains 1) directly participates in the interplay between BRCA1 and 53BP1. Mechanistically, UHRF1 is recruited to DNA double-strand breaks (DSBs) by BRCA1 in S phase, which requires the BRCT domain of BRCA1 and phosphorylated Ser674 of UHRF1. Subsequently, UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation. Thus, UHRF1 is a key regulator of DSB repair choice, which is separate from its role in heterochromatin formation and epigenetic regulator.

引用

页数：14

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