p53 Inactivation by HPV16 E6 Results in Increased Mutagenesis in Human Cells

Pamela A. Havre, Jianling Yuan, Peter M. Glazer, Lora Hedrick, Kathleen R. Cho

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186 Scopus citations

Abstract

To study the pathways associated with genomic instability in cancer, we examined UV-induced and spontaneous mutagenesis in clonal cell lines expressing human papillomavirus (HPV) proteins, either high-risk (HPV16) E6 or E7 or low-risk (HPV11) E6, in comparison to the parental RKO cells, a colon carcinoma cell line expressing only normal p53. High-risk E6 and E7 bind and functionally inactivate tumor suppressor proteins p53 and Rb, respectively, and both disrupt the G1 arrest in response to DNA damage. Low-risk HPV E6 proteins bind p53 with much lower affinity than high-risk E6 and fail to mediate p53 degradation or to disrupt the G1 checkpoint. We found that cells expressing HPV16 E6 had reduced survival and increased mutagenesis at the hprt locus when treated with low doses of UV. However, this analysis was complicated by the unexpected observation of a very high background of spontaneous mutagenesis in the unirradiated cells expressing the HPV16 E6 gene. Fluctuation analysis revealed a 5-fold elevated mutation rate in the cells expressing HPV16 E6. HPV11 E6 conferred a 2-fold elevation in the mutation rate, but HPV16 E7 had no effect. The increased spontaneous mutagenesis, therefore, appeared to be mediated by p53 inactivation and to be independent of Rb (which acts downstream of p53 in the G1 arrest pathway following DNA damage). Taken together, these findings suggest that the effect of p53 inactivation on spontaneous mutagenesis is manifested at the level of DNA repair, recombination, or coupling of transcription with one of these processes instead of by an alteration in G1 arrest.

Original languageEnglish (US)
Pages (from-to)4420-4424
Number of pages5
JournalCancer Research
Volume55
Issue number19
StatePublished - Oct 1 1995

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    Havre, P. A., Yuan, J., Glazer, P. M., Hedrick, L., & Cho, K. R. (1995). p53 Inactivation by HPV16 E6 Results in Increased Mutagenesis in Human Cells. Cancer Research, 55(19), 4420-4424.