BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells

Cancer Res. 2000 Oct 1;60(19):5548-52.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • BRCA1 Protein / biosynthesis
  • BRCA1 Protein / deficiency
  • BRCA1 Protein / physiology*
  • BRCA2 Protein
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Transformed
  • DNA Damage
  • DNA Repair / genetics
  • DNA Repair / physiology*
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / physiology
  • Genes, BRCA1 / physiology
  • Genetic Vectors
  • Germ-Line Mutation
  • Guanine / analogs & derivatives*
  • Guanine / metabolism*
  • Humans
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Oxidative Stress
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • RNA Polymerase II / antagonists & inhibitors
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transcription, Genetic / genetics
  • Transcription, Genetic / physiology*
  • Transfection

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • Neoplasm Proteins
  • Recombinant Proteins
  • Transcription Factors
  • 8-hydroxyguanine
  • Guanine
  • RNA Polymerase II