Cis-acting Elements in the Regulation of Papillomavirus Gene Expression

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Infections with human papillomaviruses (HPVs) are the most common sexually transmitted infection in the US. These infections cause an estimated 5% of cancers worldwide. HPV infects the basal keratinocytes of differentiating epithelial tissues. Importantly, only persistent HPV infections are responsible for cancer. Thus, understanding the virus-host interplay that influences viral persistence has important implications for HPV biology and human cancers. We used a single-cell genomics approach to identify protein arginine N-methyltransferase 1 (PRMT1) as an important factor for persistence of viral infection within primary human cervical cells. We demonstrate that PRMT1 inhibition increases the deposition of m6A marks on HPV18 viral mRNA, specifically to intronic regions, resulting in overall dysregulated splicing of the viral genes. We hypothesize that PRMT1 regulates RBM15 controlled m6a deposition on viral mRNA to regulate alternative splicing during persistent infection. PRMTs have recently emerged as molecular targets for anticancer drug development. Although many candidates are still in the preclinical stage, some inhibitors have entered clinical trials. The basic research in this project determines if PRMT inhibitors could have translational use for HPV infections and tumors.