BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation
| Autor: | Ryota Sekine, Yoshihiko Hagiwara, Takashi Nakano, Takahiro Oike, Ryotaro Nishi, Chikashi Obuse, Mayu Isono, Elena Petricci, Shinichiro Nakada, Atsushi Shibata, Hiro Sato, Shin Ya Isobe, Atsuko Niimi, Yukari Yoshida |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetics and Molecular Biology (all) DNA Repair RAD51 Ataxia Telangiectasia Mutated Proteins Biochemistry S Phase chemistry.chemical_compound Endonuclease RIF1 HR Phosphoprotein Phosphatases DNA Breaks Double-Stranded Phosphorylation Homologous Recombination lcsh:QH301-705.5 MRE11 Homologue Protein BRCA1 Protein Nuclear Proteins 53BP1 DNA-end resection Tumor Suppressor p53-Binding Protein 1 Signal Transduction G2 Phase Telomere-Binding Proteins Phosphatase Biology General Biochemistry Genetics and Molecular Biology Resection Dephosphorylation 03 medical and health sciences Humans NHEJ Endodeoxyribonucleases BRCA1 ATM PP4C Biochemistry Genetics and Molecular Biology (all) DNA Repair Enzymes Exodeoxyribonucleases 030104 developmental biology lcsh:Biology (General) chemistry Cancer research biology.protein bacteria Carrier Proteins Homologous recombination DNA |
| Zdroj: | Cell Reports, Vol 18, Iss 2, Pp 520-532 (2017) |
| Popis: | Summary: 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. : Following induction of DNA double-strand break, a pro-end-joining environment is created in G2 by transient 53BP1 phosphorylation and RIF1 recruitment. Here, Isono et al. show that, if timely repair does not ensue, BRCA1 promotes 53BP1 dephosphorylation and RIF1 release, favoring repair by homologous recombination. Keywords: ATM, DNA-end resection, BRCA1, 53BP1, RIF1, PP4C, NHEJ, HR |
| Databáze: | OpenAIRE |
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