DOI: 10.1101/522250Jan 16, 2019Paper

SAMHD1 regulates human papillomavirus 16 induced cell proliferation and viral replication during differentiation of oral keratinocytes.

BioRxiv : the Preprint Server for Biology
Iain M MorganRenfeng Li

Abstract

Human papillomaviruses induce a host of anogenital cancers, and also oropharyngeal cancer (HPV+OPC); HPV16 is causative in around 90% of HPV+OPC. Using TERT immortalized 'normal' oral keratinocytes (NOKs) we have identified significant host gene reprogramming by HPV16 (NOKs+HPV16), and demonstrated that NOKs+HPV16 support late stages of the viral life cycle. Expression of the cellular dNTPase and homologous recombination factor SAMHD1 is transcriptionally regulated by HPV16 in NOKs, and here we demonstrate that E6 and E7 regulate expression of SAMHD1 at the transcriptional and post-transcriptional levels. CRISPR/Cas9 removal of SAMHD1 from NOKs and NOKs+HPV16 demonstrate that SAMHD1 controls cell proliferation of NOKs only in the presence of HPV16; deletion of SAMHD1 promotes hyper-proliferation of NOKs+HPV16 cells in organotypic raft cultures but has no effect on NOKs. Viral replication is also elevated in the absence of SAMHD1. This new system has allowed us to identify a specific interaction between SAMHD1 and HPV16 that regulates host cell proliferation and viral replication; such studies are problematic in non-immortalized primary oral keratinocytes due to their limited lifespan. To confirm the relevance of our results we ...Continue Reading

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