title: Cell cycle-dependent inhibition of 53BP1 signaling by BRCA1.
abstract: DNA damage response mediator protein 53BP1 is a key regulator of non-homologous end-joining (NHEJ) repair. 53BP1 protects DNA broken ends from resection by recruiting two downstream factors, RIF1 (RAP1-interacting factor 1) and PTIP (Pax transactivation domain-interacting protein), to double-stranded breaks (DSBs) via ATM (ataxia telangiectasia mutated)-mediated 53BP1 phosphorylation, and competes with BRCA1-mediated homologous recombination (HR) repair in G1 phase. In contrast, BRCA1 antagonizes 53BP1-direct NHEJ repair in S/G2 phases. We and others have found that BRCA1 prevents the translocation of RIF1 to DSBs in S/G2 phases; however, the underlying mechanism remains unclear. Here we show that efficient ATM-dependent 53BP1 phosphorylation is restricted to the G1 phase of the cell cycle, as a consequence RIF1 and PTIP accumulation at DSB sites only occur in G1 phase. Mechanistically, both BRCT and RING domains of BRCA1 are required for the inhibition of 53BP1 phosphorylation in S and G2 phases. Thus, our findings reveal how BRCA1 antagonizes 53BP1 signaling to ensure that HR repair is the dominant repair pathway in S/G2 phases.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; State Key Laboratory for Biocontrol and Key Laboratory of Gene Engineering of Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Systems Biomedicine, Medical Isotopes Research Center, School of Basic Medical Sciences, Peking University , Beijing, China.
authors.forename: Jiadong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
keywords: 53BP1; ATM; BRCA1; DNA repair choice; PTIP; RIF1; cell cycle; homologous recombination