title: BRCA1 modulates the autophosphorylation status of DNA-PKcs in S phase of the cell cycle.
abstract: Non-homologous end-joining (NHEJ) and homologous recombination (HR) are the two prominent pathways responsible for the repair of DNA double-strand breaks (DSBs). NHEJ is not restricted to a cell-cycle stage, whereas HR is active primarily in the S/G2 phases suggesting there are cell cycle-specific mechanisms that play a role in the choice between NHEJ and HR. Here we show NHEJ is attenuated in S phase via modulation of the autophosphorylation status of the NHEJ factor DNA-PKcs at serine 2056 by the pro-HR factor BRCA1. BRCA1 interacts with DNA-PKcs in a cell cycle-regulated manner and this interaction is mediated by the tandem BRCT domain of BRCA1, but surprisingly in a phospho-independent manner. BRCA1 attenuates DNA-PKcs autophosphorylation via directly blocking the ability of DNA-PKcs to autophosphorylate. Subsequently, blocking autophosphorylation of DNA-PKcs at the serine 2056 phosphorylation cluster promotes HR-required DNA end processing and loading of HR factors to DSBs and is a possible mechanism by which BRCA1 promotes HR.
authors.affiliation: Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Rd, Dallas, TX 75390, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Davis
authors.affiliation: The First Affiliated Hospital, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Chi
authors.affiliation: Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Rd, Dallas, TX 75390, USA.
authors.forename: Sairei
authors.initials: S
authors.lastname: So
authors.affiliation: Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Rd, Dallas, TX 75390, USA.
authors.forename: Kyung-Jong
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Rd, Dallas, TX 75390, USA.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Mori
authors.affiliation: Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Rd, Dallas, TX 75390, USA.
authors.forename: Kazi
authors.initials: K
authors.lastname: Fattah
authors.affiliation: The First Affiliated Hospital, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China Department of Toxicology, Hangzhou Normal University School of Public Health, 16 Xue Lin Street, Hangzhou, Zhejiang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Rd, Dallas, TX 75390, USA david.chen@utsouthwestern.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chen
mesh_terms: D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D051747:DNA-Activated Protein Kinase / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011836:Radiation Tolerance; D059767:Recombinational DNA Repair; D016196:S Phase / Q000235:genetics; D012694:Serine / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D012694:Serine; D051747:DNA-Activated Protein Kinase