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

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


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.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • BRCA1 Protein / metabolism*
  • Carrier Proteins / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Repair Enzymes / metabolism
  • DNA Repair*
  • Endodeoxyribonucleases
  • Exodeoxyribonucleases / metabolism
  • G2 Phase
  • Homologous Recombination*
  • Humans
  • MRE11 Homologue Protein / metabolism
  • Nuclear Proteins / metabolism
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • S Phase
  • Signal Transduction*
  • Telomere-Binding Proteins / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / metabolism*


  • BRCA1 Protein
  • BRCA1 protein, human
  • Carrier Proteins
  • MRE11 protein, human
  • Nuclear Proteins
  • Rif1 protein, human
  • TP53BP1 protein, human
  • Telomere-Binding Proteins
  • Tumor Suppressor p53-Binding Protein 1
  • Ataxia Telangiectasia Mutated Proteins
  • EXO1 protein, human
  • Endodeoxyribonucleases
  • Exodeoxyribonucleases
  • MRE11 Homologue Protein
  • RBBP8 protein, human
  • Phosphoprotein Phosphatases
  • protein phosphatase 4
  • DNA Repair Enzymes