Abstract
SummaryThe 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.
Highlights
DNA double-strand breaks (DSBs) are highly toxic lesions that form when both strands of the DNA duplex are disrupted simultaneously
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 50 end resection, but how this is achieved remains uncertain
We report that Rif1À/À mice are severely compromised for 53BP1-dependent class switch recombination (CSR) and fusion of dysfunctional telomeres
Summary
DNA double-strand breaks (DSBs) are highly toxic lesions that form when both strands of the DNA duplex are disrupted simultaneously. DSBs can be programmed and are essential during meiosis for promoting exchange between homologous chromosomes to generate genetic diversity and to ensure correct chromosome segregation at meiosis I (Youds and Boulton, 2011). The repair of programmed DSBs is essential for the production of a full immune repertoire during V(D)J recombination and class switch recombination (CSR) (Stavnezer et al, 2008). DSBs exist at the end of all linear chromosomes but are normally protected by the telomere and its binding proteins from erroneous repair (de Lange, 2005). Failure to correctly repair DSBs or defects in telomere maintenance have been linked to numerous genetic disorders associated with genome instability, cancer predisposition, accelerated aging, and immune deficiency (Jackson and Bartek, 2009; McKinnon, 2009)
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