BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids

Nat Commun. 2013;4:2404. doi: 10.1038/ncomms3404.

Abstract

BRCA1 controls early steps of the synthesis-dependent strand annealing (SDSA) pathway of homologous recombination, but has no known role following Rad51-mediated synapsis. Here we show that BRCA1 influences post-synaptic homologous recombination events, controlling the balance between short- (STGC) and long-tract gene conversion (LTGC) between sister chromatids. Brca1 mutant cells reveal a bias towards LTGC that is corrected by expression of wild-type but not cancer-predisposing BRCA1 alleles. The LTGC bias is enhanced by depletion of CtIP but reversed by inhibition of 53BP1, implicating DNA end resection as a contributor to the STGC/LTGC balance. The impact of BRCA1/CtIP loss on the STGC/LTGC balance is abolished when the second (non-invading) end of the break is unable to support termination of STGC by homologous pairing (annealing). This suggests that BRCA1/CtIP-mediated processing of the second end of the break controls the annealing step that normally terminates SDSA, thereby suppressing the error-prone LTGC outcome.

Publication types

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

MeSH terms

  • Alleles
  • BRCA1 Protein / metabolism*
  • Carrier Proteins / metabolism*
  • Chromatids / genetics*
  • Crossing Over, Genetic
  • DNA Breaks, Double-Stranded
  • DNA Repair / genetics
  • Endodeoxyribonucleases
  • Flow Cytometry
  • Gene Conversion*
  • Genes, Reporter
  • Genetic Complementation Test
  • Humans
  • Models, Biological
  • Mutation / genetics
  • Nuclear Proteins / metabolism*
  • RNA, Small Interfering / metabolism

Substances

  • BRCA1 Protein
  • Carrier Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • Endodeoxyribonucleases
  • RBBP8 protein, human