Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences.
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.
Tutt
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A
The Breakthrough Toby Robins, Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
Bertwistle
D
D
Valentine
J
J
Gabriel
A
A
Swift
S
S
Ross
G
G
Griffin
C
C
Thacker
J
J
Ashworth
A
A
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*
D024682:BRCA2 Protein; D005819:Genetic Markers; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors