BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells.
The breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, are likely to participate in DNA lesion processing. Oxidative lesions, such as 8-oxoguanine, occur in DNA after endogenous or exogenous oxidative stress. We show that deficiency for either BRCA1 or BRCA2 in human cancer cells leads to a block of the RNA polymerase II transcription machinery at the 8-oxoguanine site and impairs the transcription-coupled repair of the lesion, leading to a high mutation rate. Expression of wild-type BRCA1 from a recombinant adenovirus fully complements the repair defect in BRCA1-deficient cells. These results represent the first demonstration of the essential contribution of BRCA1 and BRCA2 gene products in the repair of the 8-oxoguanine oxidative damage specifically located on the transcribed strand in human cells. This suggests that cells from individuals predisposed to breast and/or ovarian cancer may undergo a high rate of mutations because of the deficiency of this damage repair pathway after oxidative stress.
Le Page
F
F
Laboratory of Genetic Instability and Cancer, UPR 2169 CNRS, Villejuif, France.
Randrianarison
V
V
Marot
D
D
Cabannes
J
J
Perricaudet
M
M
Feunteun
J
J
Sarasin
A
A
D000256:Adenoviridae / Q000235:genetics; D019313:BRCA1 Protein / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D019398:Genes, BRCA1 / Q000502:physiology; D005822:Genetic Vectors; D018095:Germ-Line Mutation; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C024829:8-hydroxyguanine; D006147:Guanine; D012319:RNA Polymerase II