Cis-acting Elements in the Regulation of Papillomavirus Gene Expression

人乳头瘤病毒（HPV）感染是最常见的性传播疾病。 在美国感染。这些感染导致全球约5%的癌症。 HPV感染分化上皮组织的基底角质形成细胞。重要的是，只有坚持 HPV感染是导致癌症的原因。因此，了解病毒与宿主的相互作用， 影响病毒持久性对HPV生物学和人类癌症具有重要意义。 我们使用单细胞基因组学方法鉴定蛋白质精氨酸N-甲基转移酶1 PRMT 1作为原发性人类宫颈内病毒感染持续存在的重要因素 细胞我们证明PRMT 1抑制增加了HPV 18上m6 A标记的沉积， 病毒mRNA，特别是内含子区域，导致病毒的整体剪接失调， 基因.我们假设PRMT 1调节RBM 15控制的m6 a在病毒mRNA上的沉积， 在持续感染中调节可变剪接。PRMT最近出现， 抗癌药物开发的分子靶点。尽管许多候选人仍在 临床前阶段，一些抑制剂已进入临床试验。本项目的基础研究 确定PRMT抑制剂是否可以用于HPV感染和肿瘤的翻译用途。

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.