HPV Episome Stability is Reduced by Aphidicolin and Controlled by DNA Damage Response Pathways.

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HPV Episome Stability is Reduced by Aphidicolin and Controlled by DNA Damage Response Pathways.

J Virol. 2013 Jan 30;

Authors: Edwards TG, Helmus MJ, Koeller K, Bashkin JK, Fisher C

Abstract
A highly reproducible Q-PCR assay was used to study the stability of HPV in undifferentiated keratinocytes that maintain viral episomes. Stability refers to the ability of episomes to persist with little copy number variation in cells. In investigating the mechanism of action of PA25, a previously published compound that destabilizes HPV episomes, aphidicolin was also found to markedly decrease episome levels, but via a different pathway than PA25. Since aphidicolin is known to activate DNA damage response (DDR) pathways, effects of inhibitors and siRNAs acting within DDR pathways were investigated. Inhibitors of Chk1 and siRNA directed against ATR significantly reduced viral episomes suggesting that these pathways play a role in maintaining HPV episome stability. Inhibitors of Chk2 and DNA-PK had no effect on episome levels. Pharmacological ATM inhibition had no effect on episome levels, but ATM knockdown by siRNA significantly reduced episomes, suggesting that ATM is playing an important role in HPV episome stability that does not require kinase activity. These results outline two pathways that trigger episome loss from cells and suggest the existence of a little understood mechanism that mediates viral DNA elimination. Together, our results also indicate that HPV episomes have a stability profile that is remarkably similar to that of fragile sites; these similarities are outlined and discussed. This close correspondence may influence the preference of HPV for integration into fragile sites.

PMID: 23365423 [PubMed - as supplied by publisher]

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