BRCA1 transcriptionally regulates damaged DNA binding protein (DDB2) in the DNA repair response following UV-irradiation

Cancer Biol Ther. Mar-Apr 2002;1(2):177-86. doi: 10.4161/cbt.65.

Abstract

The p53 and BRCA1 tumor suppressors are involved in repair processes and may cooperate to transactivate certain genes, including p21WAF/CIP1 and GADD45. We find that the Xeroderma Pigmentosum Complementation group E (XPE) mutated Damaged-DNA binding protein p48 (DDB2) is upregulated by BRCA1 in a p53-dependent manner following UVC, Adriamycin, or Cisplatin exposure. BRCA1 enhances p53 binding to the DDB2 promoter in vivo as well as p53-dependent transactivation of DDB2 promoter-reporter constructs through a classical p53 DNA responsive element. Antisense abrogation of BRCA1 expression abrogates upregulation of DDB2 after UVC or cisplatin exposure. Using a host cell reactivation assay, DNA repair activity is more significantly restored by introduction of BRCA1 into wt as compared to DDB2-deficient cells. Furthermore disappearance of the photoproducts cyclobutane pyrimidine dimer (CPD) and 6-4 photoproduct (6-4PP) was delayed by antisense abrogation of BRCA1 expression in UV-exposed human cells. Thus the DNA repair function of BRCA1 may be attributed in part to p53-dependent transcriptional induction of DDB2. Loss of BRCA1-dependent DDB2 repair function may contribute to cancer susceptibility and cellular sensitivity to DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival
  • DNA Damage
  • DNA Repair*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology
  • Gene Expression Regulation
  • Genes, BRCA1 / physiology*
  • Genes, p53 / physiology
  • Humans
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • Ultraviolet Rays

Substances

  • DDB2 protein, human
  • DNA-Binding Proteins