Article
- The EMBO Journal (2001) 20, 4704 - 4716
- doi:10.1093/emboj/20.17.4704
Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences
Andrew Tutt1, David Bertwistle1, Janet Valentine1, Anastasia Gabriel1, Sally Swift1, Gillian Ross1, Carol Griffin2, John Thacker2 and Alan Ashworth1
- The Breakthrough Toby Robins, Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB UK
- Medical Research Council Radiation and Genome Stability Unit, Harwell OX11 0RD, UK
Correspondence to:
Alan Ashworth, E-mail: alana@icr.ac.uk
Received 16 May 2001; Accepted 13 July 2001; Revised 13 July 2001
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.
Keywords:
- BRCA2,
- DNA repair,
- homologous recombination,
- single-strand annealing,
- sister chromatid exchange
