title: BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair.
abstract: Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA crosslink repair that is distinct from HR. Disruption of the nonhomologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed by ablation of 53BP1 or Ku.
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Bunting
authors.forename: Elsa
authors.initials: E
authors.lastname: Callén
authors.forename: Marina L
authors.initials: ML
authors.lastname: Kozak
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Nancy
authors.initials: N
authors.lastname: Wong
authors.forename: Andrés J
authors.initials: AJ
authors.lastname: López-Contreras
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Richard
authors.initials: R
authors.lastname: Baer
authors.forename: Robert B
authors.initials: RB
authors.lastname: Faryabi
authors.forename: Amy
authors.initials: A
authors.lastname: Malhowski
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Chen
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
authors.forename: Alan
authors.initials: A
authors.lastname: D'Andrea
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000502:physiology; D019313:BRCA1 Protein / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D059765:Homologous Recombination / Q000502:physiology*; D000072200:Ku Autoantigen; D051379:Mice; D017384:Sequence Deletion
chemical_list: D034961:Antigens, Nuclear; D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen