Involvement of Brca2 in DNA repair.
Abnormalities precipitated by a targeted truncation in the murine gene Brca2 define its involvement in DNA repair. In culture, cells harboring truncated Brca2 exhibit a proliferative impediment that worsens with successive passages. Arrest in the G1 and G2/M phases is accompanied by elevated p53 and p21 expression. Increased sensitivity to genotoxic agents, particularly ultraviolet light and methylmethanesulfonate, shows that Brca2 function is essential for the ability to survive DNA damage. But checkpoint activation and apoptotic mechanisms are largely unaffected, thereby implicating Brca2 in repair. This is substantiated by the spontaneous accumulation of chromosomal abnormalities, including breaks and aberrant chromatid exchanges. These findings define a function of Brca2 in DNA repair, whose loss precipitates replicative failure, mutagen sensitivity, and genetic instability reminiscent of Bloom syndrome and Fanconi anemia.
Patel
K J
KJ
Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.
Yu
V P
VP
Lee
H
H
Corcoran
A
A
Thistlethwaite
F C
FC
Evans
M J
MJ
Colledge
W H
WH
Friedman
L S
LS
Ponder
B A
BA
Venkitaraman
A R
AR
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D024682:BRCA2 Protein; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004247:DNA / Q000235:genetics; D004249:DNA Damage / Q000502:physiology; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D005333:Fetus / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects; D015870:Gene Expression / Q000502:physiology; D008099:Liver / Q000166:cytology; D051379:Mice; D016296:Mutagenesis / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics*; D011995:Recombination, Genetic / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D045567:VDJ Recombinases
D024682:BRCA2 Protein; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D004247:DNA; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases