BRCA1 Mutational Complementation Induces Synthetic Viability

Mol Cell. 2020 Jun 4;78(5):951-959.e6. doi: 10.1016/j.molcel.2020.04.006. Epub 2020 Apr 30.


BRCA1 promotes the DNA end resection and RAD51 loading steps of homologous recombination (HR). Whether these functions can be uncoupled, and whether mutant proteins retaining partial activity can complement one another, is unclear and could affect the severity of BRCA1-associated Fanconi anemia (FA). Here we generated a Brca1CC mouse with a coiled-coil (CC) domain deletion. Brca1CC/CC mice are born at low frequencies, and post-natal mice have FA-like abnormalities, including bone marrow failure. Intercrossing with Brca1Δ11, which is homozygous lethal, generated Brca1CC/Δ11 mice at Mendelian frequencies that were indistinguishable from Brca1+/+ mice. Brca1CC and Brca1Δ11 proteins were individually responsible for counteracting 53BP1-RIF1-Shieldin activity and promoting RAD51 loading, respectively. Thus, Brca1CC and Brca1Δ11 alleles represent separation-of-function mutations that combine to provide a level of HR sufficient for normal development and hematopoiesis. Because BRCA1 activities can be genetically separated, compound heterozygosity for functional complementary mutations may protect individuals from FA.

Publication types

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

MeSH terms

  • Animals
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Exons
  • Fanconi Anemia / genetics
  • Fanconi Anemia / metabolism
  • Female
  • HEK293 Cells
  • Homologous Recombination / genetics*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / genetics*
  • Tumor Suppressor p53-Binding Protein 1 / metabolism


  • BRCA1 Protein
  • BRCA1 protein, human
  • Brca1 protein, mouse
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Rad51 Recombinase