TY - JOUR
T1 - BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation
AU - Isono, Mayu
AU - Niimi, Atsuko
AU - Oike, Takahiro
AU - Hagiwara, Yoshihiko
AU - Sato, Hiro
AU - Sekine, Ryota
AU - Yoshida, Yukari
AU - Isobe, Shin Ya
AU - Obuse, Chikashi
AU - Nishi, Ryotaro
AU - Petricci, Elena
AU - Nakada, Shinichiro
AU - Nakano, Takashi
AU - Shibata, Atsushi
N1 - Funding Information:
We greatly appreciate support from and fruitful discussion with Penny A. Jeggo during editing of the manuscript. We thank Ryo Sakasai for their helpful discussions. We thank Yoshimi Omi, Yoko Hayashi, Shiho Nakanishi, and Yuka Kimura for their assistance with laboratory work. This study was supported by the Takeda Science Foundation, the Suzuken Memorial Foundation, the Uehara Memorial Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Kowa Life Science Foundation, the Sumitomo Foundation and JSPS KAKENHI Grants JP26701005 and JP26670549 (to A.S.), JP26241014 (to S.N.), JP15H02816 (to A.N.), JP20114006 and JP25116004 (to C.O.), and JP16H05888 (to R.N.).
Publisher Copyright:
© 2017 The Author(s)
PY - 2017/1/10
Y1 - 2017/1/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2016.12.042
DO - 10.1016/j.celrep.2016.12.042
M3 - Article
C2 - 28076794
AN - SCOPUS:85009211786
VL - 18
SP - 520
EP - 532
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 2
ER -