DigitalUM :: Browsing by Subject "RIF1"

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Open Access
RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection
(Cell Press, 2013-03-07) Chapman, J Ross; Barral, Patricia; Vannier, Jean-Baptiste; Borel, Valerie; Steger, Martin; Tomas-Loba, Antonia; Sartori, Alessandro A; Adams, Ian R; Batista, Facundo D; Boulton, Simon J; Fisiología
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. Here we report that Rif1 / mice are severely compromised for 53BP1-dependent class switch recombination (CSR) and fusion of dysfunc- tional telomeres. The inappropriate accumulation of RIF1 at DSBs in S phase is antagonized by BRCA1, and deletion of Rif1 suppresses toxic nonhomolo- gous end joining (NHEJ) induced by PARP inhibition in Brca1-deficient cells. Mechanistically, RIF1 is re- cruited 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.