title: RIF1 counteracts BRCA1-mediated end resection during DNA repair.
abstract: BRCA1 promotes homologous recombination repair and antagonizes 53BP1-dependent nonhomologous end joining (NHEJ) pathway. However, the molecular basis of the competition between BRCA1 and 53BP1 pathways remains elusive. Here we report that RIF1 protein translocates to damage sites via ATM-dependent 53BP1 phosphorylation. Strikingly, loss of RIF1 rescues initial DNA end resection and checkpoint activation in BRCA1-depleted cells. Interestingly RIF1 accumulation at damage sites is antagonized by BRCA1 in S and G2 phases. Conversely, the translocation of BRCA1 to damage sites is inhibited by RIF1 in G1 phase. However, loss of RIF1 differs from that of 53BP1 deficiency, as it cannot fully rescue RAD51 foci formation, homologous recombination defect, and radio-hypersensitivity in BRCA1-deficient cells. This is likely because RIF1, but not 53BP1, also regulates the foci formation and chromatin loading of BLM (the Bloom syndrome helicase). Thus, RIF1 not only acts downstream of 53BP1 and counteracts BRCA1-mediated end resection but also has a secondary role in promoting BLM function in DNA repair.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Feng
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Fong
authors.forename: Jiadong
authors.initials: J
authors.lastname: Wang
authors.forename: Wenqi
authors.initials: W
authors.lastname: Wang
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology; D016195:G2 Phase / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000502:physiology; D000071857:Tumor Suppressor p53-Binding Protein 1; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C097151:Bloom syndrome protein; C419867:RHOF protein, human; D053484:RecQ Helicases; D020741:rho GTP-Binding Proteins