BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair

Mol Cell. 2012 Apr 27;46(2):125-35. doi: 10.1016/j.molcel.2012.02.015. Epub 2012 Mar 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Nuclear / physiology
  • BRCA1 Protein / genetics
  • BRCA1 Protein / physiology*
  • DNA Repair*
  • DNA-Binding Proteins / physiology
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Gene Knockdown Techniques
  • Genomic Instability
  • Homologous Recombination / physiology*
  • Ku Autoantigen
  • Mice
  • Sequence Deletion


  • Antigens, Nuclear
  • BRCA1 Protein
  • DNA-Binding Proteins
  • Fancd2 protein, mouse
  • Fanconi Anemia Complementation Group D2 Protein
  • Xrcc6 protein, mouse
  • Ku Autoantigen

Associated data

  • GEO/GSE35698