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Cell Rep. 2017 Jan 10;18(2):520-532. doi: 10.1016/j.celrep.2016.12.042.

BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation.

Author information

1
Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan; Gunma University Heavy Ion Medical Center, Gunma University, Maebashi, Gunma 371-8511, Japan.
2
Gunma University Initiative for Advanced Research, Gunma University, Maebashi, Gunma 371-8511, Japan.
3
Department of Radiation Oncology, Gunma University, Maebashi, Gunma 371-8511, Japan.
4
Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan; Department of Radiation Oncology, Gunma University, Maebashi, Gunma 371-8511, Japan.
5
Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan.
6
Gunma University Heavy Ion Medical Center, Gunma University, Maebashi, Gunma 371-8511, Japan.
7
Graduate School of Life Science, Hokkaido University, Sapporo, Hokkaido 060-0810, Japan.
8
Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan.
9
Department of Biotechnology, Chemistry, and Pharmacy, Università degli Studi di Siena, 53100 Siena, Italy.
10
Department of Bioregulation and Cellular Response, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
11
Gunma University Heavy Ion Medical Center, Gunma University, Maebashi, Gunma 371-8511, Japan; Gunma University Initiative for Advanced Research, Gunma University, Maebashi, Gunma 371-8511, Japan; Department of Radiation Oncology, Gunma University, Maebashi, Gunma 371-8511, Japan.
12
Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan. Electronic address: shibata.at@gunma-u.ac.jp.

Abstract

BRCA1 promotes homologous recombination (HR) by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G2 phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs). When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling. BRCA1 depletion also sustains 53BP1 phosphorylation and RIF1 recruitment. We identify the phosphatase PP4C as having a major role in 53BP1 dephosphorylation and RIF1 release. BRCA1 or PP4C depletion impairs 53BP1 repositioning, EXO1 recruitment, and HR progression. 53BP1 or RIF1 depletion restores resection, RAD51 loading, and HR in PP4C-depleted cells. Our findings suggest that BRCA1 promotes PP4C-dependent 53BP1 dephosphorylation and RIF1 release, directing repair toward HR.

KEYWORDS:

53BP1; ATM; BRCA1; DNA-end resection; HR; NHEJ; PP4C; RIF1

PMID:
28076794
DOI:
10.1016/j.celrep.2016.12.042
[Indexed for MEDLINE]
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