Cell cycle and genetic background dependence of the effect of loss of BRCA2 on ionizing radiation sensitivity.
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 (Brca2(Tr)) 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 Brca2(Tr/Tr)/p53(-/-) cells, like Brca2(Tr/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 Brca2(Tr/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 G(2) phases of the cell cycle.
Tutt
Andrew
A
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
Connor
Frances
F
Bertwistle
David
D
Kerr
Peter
P
Peacock
John
J
Ross
Gill
G
Ashworth
Alan
A
D000818:Animals; D001943:Breast Neoplasms / Q000532:radiotherapy; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D018385:Centrosome / Q000528:radiation effects; D005260:Female; D024522:Genes, BRCA2; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009154:Mutation; D011836:Radiation Tolerance / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D016159:Tumor Suppressor Protein p53