Cooperation between BRCA1 and p53 in repair of cyclobutane pyrimidine dimers.
DNA repair defects can predispose to cancer development and progression. We previously showed that the breast and ovarian cancer susceptibility gene product BRCA1, through p53, upregulates expression of the XPE gene DDB2 encoding the nucleotide excision repair protein p 48. Both XPE and XPC are p53 target genes containing p53 response elements. To further explore the role of BRCA1 and p53 in repair of photoproducts, we eliminated wild type p53 from U2OS osteosarcoma cells and found that cyclobutane pyrimidine dimer (CPD) repair was markedly impaired following UV damage whereas repair of 6-4 photoproduct (6-4 PP) occurred efficiently. Overexpression of p53 in p53-null Calu-6 cells also enhanced CPD repair. In HCC1937 breast cancer cells, harboring mutant BRCA1 and p53 genes, repair of CPD was markedly impaired. Reintroduction of either p53 or BRCA1 using adenovirus vectors into HCC1937 alone had little effect on repair of CPD whereas the combination of p53 and BRCA1 resulted in efficient repair of CPD. Thus there appears to be a cooperative effect between p53 and BRCA1 that may involve induction of repair proteins, inhibition of p53-induced cell death by BRCA1 with altered p53 selectivity towards repair pathways and/or p53-independent effects of BRCA1 on CPD repair.
Navaraj
Arunasalam
A
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Mori
Toshio
T
El-Deiry
Wafik S
WS
D019313:BRCA1 Protein / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D011740:Pyrimidine Dimers / Q000235:genetics* / Q000528:radiation effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics
D019313:BRCA1 Protein; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D011740:Pyrimidine Dimers; D016159:Tumor Suppressor Protein p53