RIF1 Counteracts BRCA1-mediated End Resection during DNA Repair

Abstract

Background: 53BP1 counteracts BRCA1 in DNA repair. Results: RIF1 acts downstream of 53BP1 and counteracts BRCA1 in DNA end resection. It also has a 53BP1-independent role in regulating BLM chromatin association. Conclusion: RIF1 is the major downstream effector of 53BP1. Significance: These results reveal that RIF1 antagonizes BRCA1, functions in DNA end protection, and prevents homologous recombination repair.

53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks

“…The observation that loss of RIF1 only partially restores HR in cells lacking BRCA1 (75) suggested that another protein may be involved in the attenuation of HR to favor NHEJ. Indeed, PTIP has recently been identified as an additional 53BP1 effector (76).…”

“…However, it is known that RIF1 interacts with the BLM helicase and is required for recruitment of BLM to foci (75,78). Conceivably, RIF1 may inhibit the ability of BLM to unwind DNA for resection by DNA2.…”

CtIP-mediated resection is essential for viability and can operate independently of BRCA1

“…It was shown that 53BP1 inhibits resection, but that BRCA1 antagonizes 53BP1, allowing the nucleolytic processing of DNA ends in S phase (Bunting et al, 2010;Chapman et al, 2012). Furthermore PTIP and RIF1, both of which act downstream of 53BP1, inhibit BRCA1-associated DNA metabolism (Callen et al, 2013;Chapman et al, 2013;EscribanoDíaz et al, 2013;Feng et al, 2013;Zimmermann et al, 2013). Nevertheless, the mediators of resection in BRCA1/53BP1, BRCA1/PTIP, and BRCA1/RIF double-deficient cells have not been identified.…”

A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci

“…The increase in HR events in cells lacking 53BP1 and RAP80/BRCA1 foci implies that inhibiting their recruitment to foci has supportive effects on HR, consistent with recent findings identifying a complex regulatory interplay between the BRCA1/RAP80 complex and 53BP1 at the level of restricting DNA end resection at sites of DSBs. [40][41][42][43][44][45][46][47] …”