Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms3404
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Funding
- NIH [CA095175, GM073894]
- T32 Training Grant in Cancer Biology [CA081156]
- ACS postdoctoral fellowship
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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.
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