title: BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids.
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.
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Gurushankar
authors.initials: G
authors.lastname: Chandramouly
authors.forename: Amy
authors.initials: A
authors.lastname: Kwok
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Willis
authors.forename: Anyong
authors.initials: A
authors.lastname: Xie
authors.forename: Ralph
authors.initials: R
authors.lastname: Scully
mesh_terms: D000483:Alleles; D019313:BRCA1 Protein / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002842:Chromatids / Q000235:genetics*; D003434:Crossing Over, Genetic; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D004706:Endodeoxyribonucleases; D005434:Flow Cytometry; D005785:Gene Conversion; D017930:Genes, Reporter; D005816:Genetic Complementation Test; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D002352:Carrier Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human