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

Haoxing Zhang, Hailong Liu, Yali Chen, Xu Yang, Panfei Wang, Tongzheng Liu, Min Deng, Bo Qin, Cristina Correia, Seungbaek Lee, Jungjin Kim, Melanie Sparks, Asha A. Nair, Debra L. Evans, Krishna R. Kalari, Pumin Zhang, Liewei Wang, Zhongsheng You, Scott H. Kaufmann, Zhenkun Lou () and Huadong Pei ()
Additional contact information
Haoxing Zhang: School of Life Sciences, Southwest University
Hailong Liu: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Yali Chen: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Xu Yang: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Panfei Wang: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Tongzheng Liu: Mayo Clinic, Rochester
Min Deng: Mayo Clinic, Rochester
Bo Qin: Mayo Clinic, Rochester
Cristina Correia: Mayo Clinic, Rochester
Seungbaek Lee: Mayo Clinic, Rochester
Jungjin Kim: Mayo Clinic, Rochester
Melanie Sparks: Washington University
Asha A. Nair: BSI-Genetics & Bioinformatics, Mayo Clinic
Debra L. Evans: Mayo Clinic, Rochester
Krishna R. Kalari: BSI-Genetics & Bioinformatics, Mayo Clinic
Pumin Zhang: Baylor College of Medicine
Liewei Wang: Molecular Pharmacology and Experimental therapeutics, Mayo Clinic
Zhongsheng You: Washington University
Scott H. Kaufmann: Mayo Clinic, Rochester
Zhenkun Lou: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Huadong Pei: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10201

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