@article{b885a7684b9a41079de6d4a1a9fcc4c4,
title = "A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice",
abstract = "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.",
author = "Haoxing Zhang and Hailong Liu and Yali Chen and Xu Yang and Panfei Wang and Tongzheng Liu and Min Deng and Bo Qin and Cristina Correia and Seungbaek Lee and Jungjin Kim and Melanie Sparks and Nair, {Asha A.} and Evans, {Debra L.} and Kalari, {Krishna R.} and Pumin Zhang and Liewei Wang and Zhongsheng You and Kaufmann, {Scott H.} and Zhenkun Lou and Huadong Pei",
note = "Funding Information: We thank all colleagues in Dr Zhenkun Lou{\textquoteright}s laboratory for insightful discussions and technical assistance. We thank Dr Dongyi Xu at Peking University for providing RIF1 constructs. We thank Dr Haojie Huang at Mayo Clinic for providing the GST-BRCA1 fragments. We thank Gr. Stark, J. M at Beckman Research Institute of the City of Hope for generously providing the intergrated DNA repair reporter system. We thank Dr Lei Li at MD Anderson Cancer Center kindly providing us independent UHRF1 hypomorphic mutants (UHRF1-/Neo-1 and UHRF1-/Neo-2). This work was supported by the grants from National Basic Research Program of China 973 Program (nos. 2012CB910300, 2015CB910600 and 2013CB910300 to H.D.P.), National Natural Science Foundation of China (nos. 31371433 and 31571463 to H.D.P.), International S&T Cooperation Program of China (nos. 2015DFA31680 to H.D.P. and 2015DFA30610 to Z.K.L.), State Key Laboratory of Proteomics (no. SKLP-O201303), One Thousand Young Talent Program to H.D.P, and NIH CA130996, CA108961 and CA148940 to Zhenkun Lou. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2016, Nature Publishing Group. All rights reserved.",
year = "2016",
month = jan,
day = "5",
doi = "10.1038/ncomms10201",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
}