Abstract
Carriers of mutations in the BRCA2 gene are at a highly elevated risk of breast and other cancers. The BRCA2 gene encodes a very large protein thought to play a role in DNA repair. To examine the effect of mutation of BRCA2 on sensitivity to ionizing radiation, we used a previously described mouse model system (Brca2Tr) in which the Brca2 open reading frame is truncated. Mouse embryo fibroblasts carrying this mutation have a proliferative defect, which we show here can be substantially rescued by genetic ablation of p53. Proliferating Brca2Tr/Tr/p53−/− cells, like Brca2Tr/Tr cells, show genomic instability. We used the clonogenic survival assay, which depends on the ability of cells to proliferate, to examine the cell cycle dependence of radiation sensitivity of Brca2Tr/Tr/p53−/− compared to p53−/− and wild-type cells. This showed that the Brca2 mutation had little effect on cells irradiated in quiescence but sensitized proliferating cells to ionizing radiation on a p53−/− background. These results suggest that the major role of Brca2 in mediating cell survival after irradiation is in the S and G2 phases of the cell cycle.
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Tutt, A., Connor, F., Bertwistle, D. et al. Cell cycle and genetic background dependence of the effect of loss of BRCA2 on ionizing radiation sensitivity. Oncogene 22, 2926–2931 (2003). https://doi.org/10.1038/sj.onc.1206522
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DOI: https://doi.org/10.1038/sj.onc.1206522
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