title: A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice.
abstract: DNA double-strand break (DSB) repair pathway choice is governed by the opposing activities of 53BP1 and BRCA1. 53BP1 stimulates nonhomologous end joining (NHEJ), whereas BRCA1 promotes end resection and homologous recombination (HR). Here we show that 53BP1 is an inhibitor of BRCA1 accumulation at DSB sites, specifically in the G1 phase of the cell cycle. ATM-dependent phosphorylation of 53BP1 physically recruits RIF1 to DSB sites, and we identify RIF1 as the critical effector of 53BP1 during DSB repair. Remarkably, RIF1 accumulation at DSB sites is strongly antagonized by BRCA1 and its interacting partner CtIP. Lastly, we show that depletion of RIF1 is able to restore end resection and RAD51 loading in BRCA1-depleted cells. This work therefore identifies a cell cycle-regulated circuit, underpinned by RIF1 and BRCA1, that governs DSB repair pathway choice to ensure that NHEJ dominates in G1 and HR is favored from S phase onward.
authors: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors: Cristina
authors: C
authors: Escribano-Díaz
authors: Alexandre
authors: A
authors: Orthwein
authors: Amélie
authors: A
authors: Fradet-Turcotte
authors: Mengtan
authors: M
authors: Xing
authors: Jordan T F
authors: JT
authors: Young
authors: Ján
authors: J
authors: Tkáč
authors: Michael A
authors: MA
authors: Cook
authors: Adam P
authors: AP
authors: Rosebrock
authors: Meagan
authors: M
authors: Munro
authors: Marella D
authors: MD
authors: Canny
authors: Dongyi
authors: D
authors: Xu
authors: Daniel
authors: D
authors: Durocher
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D059766:DNA End-Joining Repair / Q000235:genetics; D004260:DNA Repair; D004706:Endodeoxyribonucleases; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D016196:S Phase; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C492743:Rif1 protein, human; C498301:TP53BP1 protein, human; D034501:Telomere-Binding Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human