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 p21WAF1/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 p...

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Bibliographic Details
Published in:Cancer biology & therapy 2002-03, Vol.1 (2), p.177-186
Main Authors: Takimoto, Rishu, MacLachlan, Timothy K., Dicker, David T., Niitsu, Yoshiro, Mori, Toshio, El-Deiry, Wafik S.
Format: Article
Language:English
Subjects:
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
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Summary:The p53 and BRCA1 tumor suppressors are involved in repair processes and may cooperate to transactivate certain genes, including p21WAF1/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.
ISSN:1538-4047
1555-8576
DOI:10.4161/cbt.65