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

Mayu Isono; Atsuko Niimi; Takahiro Oike; Yoshihiko Hagiwara; Hiro Sato; Ryota Sekine; Yukari Yoshida; Shin Ya Isobe; Chikashi Obuse; Ryotaro Nishi; Elena Petricci; Shinichiro Nakada; Takashi Nakano; Atsushi Shibata

doi:10.1016/j.celrep.2016.12.042

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

Mayu Isono, Atsuko Niimi, Takahiro Oike, Yoshihiko Hagiwara, Hiro Sato, Ryota Sekine, Yukari Yoshida, Shin Ya Isobe, Chikashi Obuse, Ryotaro Nishi, Elena Petricci, Shinichiro Nakada, Takashi Nakano, Atsushi Shibata

Molecular Oncology

Research output: Contribution to journal › Article

54 Citations (Scopus)

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.

Original language	English
Pages (from-to)	520-532
Number of pages	13
Journal	Cell Reports
Volume	18
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2016.12.042
Publication status	Published - 10-01-2017

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2016.12.042

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Isono, M., Niimi, A., Oike, T., Hagiwara, Y., Sato, H., Sekine, R., Yoshida, Y., Isobe, S. Y., Obuse, C., Nishi, R., Petricci, E., Nakada, S., Nakano, T., & Shibata, A. (2017). BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation. Cell Reports, 18(2), 520-532. https://doi.org/10.1016/j.celrep.2016.12.042

Isono, Mayu ; Niimi, Atsuko ; Oike, Takahiro ; Hagiwara, Yoshihiko ; Sato, Hiro ; Sekine, Ryota ; Yoshida, Yukari ; Isobe, Shin Ya ; Obuse, Chikashi ; Nishi, Ryotaro ; Petricci, Elena ; Nakada, Shinichiro ; Nakano, Takashi ; Shibata, Atsushi. / BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation. In: Cell Reports. 2017 ; Vol. 18, No. 2. pp. 520-532.

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title = "BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation",

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.",

author = "Mayu Isono and Atsuko Niimi and Takahiro Oike and Yoshihiko Hagiwara and Hiro Sato and Ryota Sekine and Yukari Yoshida and Isobe, {Shin Ya} and Chikashi Obuse and Ryotaro Nishi and Elena Petricci and Shinichiro Nakada and Takashi Nakano and Atsushi Shibata",

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BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation. / Isono, Mayu; Niimi, Atsuko; Oike, Takahiro; Hagiwara, Yoshihiko; Sato, Hiro; Sekine, Ryota; Yoshida, Yukari; Isobe, Shin Ya; Obuse, Chikashi; Nishi, Ryotaro; Petricci, Elena; Nakada, Shinichiro; Nakano, Takashi; Shibata, Atsushi.

In: Cell Reports, Vol. 18, No. 2, 10.01.2017, p. 520-532.

Research output: Contribution to journal › Article

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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

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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