title: Efficient repair of bulky anti-BPDE DNA adducts from non-transcribed DNA strand requires functional p53 but not p21(waf1/cip1) and pRb.
abstract: Wild-type p53 protein is known to regulate the global genomic repair (GGR), removing bulky chemical DNA adducts as well as cyclobutane pyrimidine dimers from the genome overall and from non-transcribed strands (NTS) in DNA. To investigate the role of cellular factor(s) relevant to p53 regulated DNA repair processes, we examined the repair kinetics of chemical carcinogen, anti-benzo[a]pyrene-diol epoxide (anti-BPDE), induced bulky DNA adducts in normal human mammary epithelial cells (HMECs) and HMEC transformed by human papillomavirus (HPV)-16E6 or -16E7 oncoproteins, which, respectively targets p53 or pRb proteins for degradation. The results show that the removal of anti-BPDE DNA adducts from the genome overall and NTS by GGR was significantly reduced in HPV-16E6 protein expressing cells as compared to that in normal and HPV-16E7 protein expressing cells, indicating the role of p53 and not pRb in nucleotide excision repair (NER). We further determined the potential effects of the p53-regulated p21(waf1/cip1) gene product in NER in human colon carcinoma, HCT116 cells expressing wild-type p53 but different p21(waf1/cip1) genotypes (p21+/+, p21+/-, p21-/-). The results donot show a discernible difference in the removal of anti-BPDE DNA adducts from the genome overall and the transcribed strand (TS) and NTS irrespective of the presence or absence of p21(waf1/cip1) expression. Based on these results, we suggest that: (i) the wild-type p53 function but not p21(waf1/cip1) expression is necessary for GGR of chemical induced bulky DNA adducts; (ii) the Rb gene product does not play a significant role in NER; and (iii) the modulation of NER by p53 may be independent of its function in the regulation of cell cycle arrest upon chemically induced DNA damage.
authors.affiliation: Department of Radiology, The Ohio State University, Columbus 43210, USA.
authors.forename: Manzoor A
authors.initials: MA
authors.lastname: Wani
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: El-Mahdy
authors.forename: Farid M
authors.initials: FM
authors.lastname: Hamada
authors.forename: Gulzar
authors.initials: G
authors.lastname: Wani
authors.forename: Qianzheng
authors.initials: Q
authors.lastname: Zhu
authors.forename: Qi-en
authors.initials: QE
authors.lastname: Wang
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Wani
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism*; D000230:Adenocarcinoma / Q000473:pathology; D001940:Breast / Q000166:cytology; D002461:Cell Line, Transformed / Q000187:drug effects; D002472:Cell Transformation, Viral; D003110:Colonic Neoplasms / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology*; D018736:DNA Adducts / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D004273:DNA, Neoplasm / Q000187:drug effects; D004706:Endodeoxyribonucleases / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects; D029968:Escherichia coli Proteins / Q000494:pharmacology; D005260:Female; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000502:physiology; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018736:DNA Adducts; D004273:DNA, Neoplasm; C068651:E6 protein, Human papillomavirus type 16; D029968:Escherichia coli Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; C059731:oncogene protein E7, Human papillomavirus type 16; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004706:Endodeoxyribonucleases; C036385:endodeoxyribonuclease uvrABC