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The appropriate execution of DNA double-strand break (DSB) repair is critical for genome stability and tumor avoidance. 53BP1 and BRCA1 directly influence DSB repair pathway choice by regulating 5' end resection, but how this is achieved remains uncertain. Here we report that Rif1(-/-) mice are severely compromised for 53BP1-dependent class switch recombination (CSR) and fusion of dysfunctional telomeres. The inappropriate accumulation of RIF1 at DSBs in S phase is antagonized by BRCA1, and deletion of Rif1 suppresses toxic nonhomologous end joining (NHEJ) induced by PARP inhibition in Brca1-deficient cells. Mechanistically, RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination.

Original publication

DOI

10.1016/j.molcel.2013.01.002

Type

Journal article

Journal

Mol Cell

Publication Date

07/03/2013

Volume

49

Pages

858 - 871

Keywords

Animals, Chromosomal Proteins, Non-Histone, DNA, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA-Binding Proteins, HeLa Cells, Humans, Mice, Recombination, Genetic, Telomere, Telomere-Binding Proteins, Transfection, Tumor Suppressor p53-Binding Protein 1