Inhibition of RIF1 by SCAI Allows BRCA1-Mediated Repair

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. [Display omitted] •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 Following DNA double-strand breakage, 53BP1 accumulates at damaged chromatin and, together with RIF1, facilitates non-homologous end joining (NHEJ). Here, Isobe et al. find that SCAI binds to 53BP1, thus inhibiting RIF1 function. This facilitates BRCA1-mediated repair, such as homology-directed repair in S/G2, and alternative-NHEJ or resection-mediated NHEJ in G1.