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Disruption of Brca2 increases the spontaneous mutation rate in vivo : synergism with ionizing radiation
Author(s) -
Tutt Andrew N J,
van Oostrom Conny Th M,
Ross Gillian M,
van Steeg Harry,
Ashworth Alan
Publication year - 2002
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1093/embo-reports/kvf037
Subject(s) - somatic cell , germline mutation , mutation , biology , in vivo , cancer research , ionizing radiation , genetics , wild type , allele , microbiology and biotechnology , brca2 protein , dna damage , ex vivo , gene , mutant , dna , irradiation , physics , nuclear physics
The breast cancer predisposition gene BRCA2 encodes a protein involved in the repair of DNA double‐strand breaks, which arise spontaneously and following exposure to ionizing radiation (IR). To develop a mouse model that examines the effect of BRCA2 mutation and IR exposure on in vivo somatic mutation acquisition, we crossed mice with targeted disruption of Brca2 with a LacZ transgenic mutation reporter strain. Loss of both wild‐type Brca2 alleles caused a 2.3‐fold increase, equivalent to an extra 100 mutations per cell, in the in vivo acquisition of spontaneous somatic mutation by 2 weeks gestation. IR (4 Gy) had a disproportionate effect on animals homozygous for Brca2 disruption, inducing 3.4‐fold more mutations compared with wild‐type animals. These data provide the first evidence that loss of Brca2 increases in vivo somatic mutation acquisition and synergizes with IR exposure, with potential attendant implications for mammographic screening and therapeutic IR in mutation carriers.