Inhibition of RIF1 by SCAI Allows BRCA1-Mediated Repair
Shin-Ya Isobe, Koji Nagao, Naohito Nozaki, Hiroshi Kimura, Chikashi Obuse5,
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Open Access
Article Info
Publication History
Published: July 11, 2017 Accepted: June 21, 2017
Received in revised form: April 24, 2017 Received: October 7, 2016
User License
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)
Highlights
• SCAI slowly accumulates at damaged sites depending on 53BP1
• 53BP1 S/TP phosphorylation sites are critical for SCAI binding
• SCAI can inhibit RIF1 function
• SCAI facilitates BRCA1-mediated DNA repair
Summary
DNA double-strand breaks (DSBs) are repaired by either the homology-directed repair (HDR) or the non-homologous end-joining (NHEJ) pathway. RIF1 (RAP1-interacting factor homolog) was recently shown to stimulate NHEJ through an interaction with 53BP1 (p53-binding protein 1) phosphorylated at S/TQ sites, but the molecular mechanism underlying pathway choice remains unclear. Here, we show that SCAI (suppressor of cancer cell invasion) binds to 53BP1 phosphorylated at S/TP sites and facilitates HDR. Upon DNA damage, RIF1 immediately accumulates at damage sites and then gradually dissociates from 53BP1 and is subsequently replaced with SCAI. Depletion of SCAI reduces both the accumulation of HDR factors, including BRCA1 (breast cancer susceptibility gene 1), at damage sites and the efficiency of HDR, as detected by a reporter assay system. These data suggest that SCAI inhibits RIF1 function to allow BRCA1-mediated repair, which possibly includes alt -NHEJ and resection-dependent NHEJ in G1, as well as HDR in S/G2.
Keywords:
DNA double-strand breaks, BRCA1, RIF1, 53BP1, SCAI, NHEJ, HDR, alternative NHEJ, resection-dependent NHEJ, genomic instability
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