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Carcinogenesis Advance Access published online on November 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm244
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63

B.E. Ferguson-Yates, H. Li, T.K. Dong, J.L. Hsiao and D.H. Oh

Department of Dermatology, University of California, San Francisco, Dermatology Research Unit, San Francisco VA Medical Center, 4150 Clement Street, San Francisco CA 94121 USA

Corresponding author: Dennis H. Oh, Dermatology Service (190), San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA 94121 USA. Telephone: (415) 750-2091. FAX: (415) 751-3927. E-mail: ohd{at}derm.ucsf.edu

While many p53-deficient cell types are impaired in global genomic nucleotide excision repair of cyclobutane pyrimidine dimers (CPD), human epidermal keratinocytes expressing human papillomavirus type 16 E6 and E7 are p53-deficient and yet maintain repair of CPD. We hypothesized that the p53 homolog, p63, may participate in governing global repair instead of p53 in keratinocytes. Following ultraviolet radiation of E6/E7 keratinocytes, depletion of p63 but not of p73 impaired global genomic repair of CPD relative to control cells. In all cases, repair of pyrimidine(6-4)pyrimidone photoproducts, the other major ultraviolet radiation-induced DNA lesions, was unaffected. In E6/E7 keratinocytes treated with p63 siRNA, reduced global repair of CPD was associated not with reduced levels of mRNA encoding DNA damage recognition proteins but rather with decreased levels of DDB2 and XPC proteins, suggesting that p63 post-transcriptionally regulates levels of these proteins. These results indicate that global repair may be regulated at multiple levels and suggest a novel role for p63 in modulating repair of DNA damage in human keratinocytes. The results may provide insight into mechanisms of genomic stability in epithelia infected with oncogenic human papilloma viruses and may further explain the lack of increased skin cancer incidence in Li-Fraumeni syndrome.

Key Words: keratinocyte • nucleotide excision repair • p53 • p63 • ultraviolet radiation

Received July 12, 2007; revised October 3, 2007; accepted October 27, 2007.


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