Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics
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BRCA1 Protein / biosynthesis
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BRCA1 Protein / deficiency
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BRCA1 Protein / physiology*
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BRCA2 Protein
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Cell Line, Transformed
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DNA Damage
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DNA Repair / genetics
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DNA Repair / physiology*
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Female
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Fibroblasts / metabolism
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Fibroblasts / physiology
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Genes, BRCA1 / physiology
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Genetic Vectors
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Germ-Line Mutation
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Guanine / analogs & derivatives*
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Guanine / metabolism*
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Humans
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Oxidative Stress
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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RNA Polymerase II / antagonists & inhibitors
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / genetics
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcription, Genetic / genetics
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Transcription, Genetic / physiology*
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Transfection
Substances
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BRCA1 Protein
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BRCA2 Protein
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Neoplasm Proteins
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Recombinant Proteins
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Transcription Factors
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8-hydroxyguanine
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Guanine
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RNA Polymerase II