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Mutation in Brca2 stimulates error‐prone homology‐directed repair of DNA double‐strand breaks occurring between repeated sequences
Author(s) -
Tutt Andrew,
Bertwistle David,
Valentine Janet,
Gabriel Anastasia,
Swift Sally,
Ross Gillian,
Griffin Carol,
Thacker John,
Ashworth Alan
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.17.4704
Subject(s) - genetics , dna , homology (biology) , biology , mutation , computational biology , microbiology and biotechnology , gene
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.