BRCA1 transcriptionally regulates damaged DNA binding protein (DDB2) in the DNA repair response following UV-irradiation.
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.
Takimoto
Rishu
R
Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Departments of Medicine, Genetics, and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
MacLachlan
Timothy K
TK
Dicker
David T
DT
Niitsu
Yoshiro
Y
Mori
Toshio
T
el-Deiry
Wafik S
WS
D002470:Cell Survival; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation; D019398:Genes, BRCA1 / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
C117669:DDB2 protein, human; D004268:DNA-Binding Proteins