Although human cytomegalovirus (HCMV) has demonstrated oncogenic potential and the ability to enhance the level of genetic damage induced by genotoxic chemicals, the precise mechanisms through which this common virus exerts these effects is unknown. It is known that HCMV induces robust mitogenic signaling, but there is little information on how cell cycle perturbation by HCMV may contribute to the increased susceptibility of infected cells to chemical-induced genotoxicity. As part of our ongoing investigation of the mechanisms through which HCMV affects cell cycle control, we have identified the activation of multiple pathways for the proteolytic degradation of p21cip1. The proposed studies will test the hypothesis that HCMV infection affects the sensitivity of cells to butadiene-induced genetic damage, particularly through inhibition of the cell cycle arrest response to DNA damage. The effect of HCMV infection on DNA adduct formation, mutation frequency and spectrum, and cell cycle progression in cells treated with butadiene or its metabolites will be investigated in human lung cells and peripheral blood lymphocytes, and in hamster V79 cells. The proteolytic degradation of p21/cip1 and inhibition of the DNA damage-induced cell arrest will be investigated in the butadiene/HCMV-treated cells. The effect of HCMV on butadiene-induced DNA adduct formation will be studied in collaboration with the Lloyd and Van Houten laboratories using quantitative PCR assays. Mutation will be studied at the hprt locus in a collaborative study with the Ward and Postlethwait laboratories. The Muganda and Albrecht laboratories will collaborative in studying the effect of HCMV infection on p53, p21cip1, and cell cycle progression.
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