Phenotypic effects of heterozygosity for a BRCA2 mutation.
Heterozygous carriers of mutations in the BRCA2 gene have a high risk of developing breast and other cancers. In these individuals, BRCA2 appears to act as a tumour suppressor gene, in that loss of the wild type allele is frequently observed within tumours, leading to loss of BRCA2 function. Because BRCA2 functions in DNA repair via homologous recombination, this leads to genomic instability. However, it is unclear whether loss of the wild type allele is stochastic or if heterozygosity for BRCA2 mutation carries a phenotype that contributes to tumorigenic progression. Here we demonstrate that, in a specific vertebrate cell type, the chicken B cell line DT40, heterozygosity for a BRCA2 mutation has a distinct phenotype. This is characterized by a reduced growth rate, increased cell death, heightened sensitivity to specific DNA damaging agents and reduced RAD51 focus formation after irradiation. Thus in certain cell types, genome instability might be driven directly by heterozygosity for BRCA2 mutation.
Warren
Madhuri
M
Cancer Research UK Gene Function and Regulation Group, The Breakthrough Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
Lord
Christopher J
CJ
Masabanda
Julio
J
Griffin
Darren
D
Ashworth
Alan
A
D000483:Alleles; D000818:Animals; D030161:Avian Proteins; D001402:B-Lymphocytes / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics*; D016923:Cell Death; D002455:Cell Division; D002470:Cell Survival; D002645:Chickens; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D016678:Genome; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D051135:Rad51 Recombinase; D011995:Recombination, Genetic; D014162:Transfection
D030161:Avian Proteins; D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; C495150:RAD51 protein, Gallus gallus; C495153:RAD51 protein, human; D051135:Rad51 Recombinase