title: Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences.
abstract: Mutation of BRCA2 causes familial early onset breast and ovarian cancer. BRCA2 has been suggested to be important for the maintenance of genome integrity and to have a role in DNA repair by homology- directed double-strand break (DSB) repair. By studying the repair of a specific induced chromosomal DSB we show that loss of Brca2 leads to a substantial increase in error-prone repair by homology-directed single-strand annealing and a reduction in DSB repair by conservative gene conversion. These data demonstrate that loss of Brca2 causes misrepair of chromosomal DSBs occurring between repeated sequences by stimulating use of an error-prone homologous recombination pathway. Furthermore, loss of Brca2 causes a large increase in genome-wide error-prone repair of both spontaneous DNA damage and mitomycin C-induced DNA cross-links at the expense of error-free repair by sister chromatid recombination. This provides insight into the mechanisms that induce genome instability in tumour cells lacking BRCA2.
authors.affiliation: The Breakthrough Toby Robins, Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
authors.forename: A
authors.initials: A
authors.lastname: Tutt
authors.forename: D
authors.initials: D
authors.lastname: Bertwistle
authors.forename: J
authors.initials: J
authors.lastname: Valentine
authors.forename: A
authors.initials: A
authors.lastname: Gabriel
authors.forename: S
authors.initials: S
authors.lastname: Swift
authors.forename: G
authors.initials: G
authors.lastname: Ross
authors.forename: C
authors.initials: C
authors.lastname: Griffin
authors.forename: J
authors.initials: J
authors.lastname: Thacker
authors.forename: A
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D000483:Alleles; D000818:Animals; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics; D002460:Cell Line; D003001:Cloning, Molecular; D004249:DNA Damage; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005260:Female; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D015183:Restriction Mapping; D017384:Sequence Deletion; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; D005819:Genetic Markers; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors