Cis-acting Elements in the Regulation of Papillomavirus Gene Expression

乳头瘤病毒基因表达调控中的顺式作用元件

基本信息

批准号：
10574199
负责人：
Koenraad Van Doorslaer
金额：
$ 22.38万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-18 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10574199
关键词：
Address Adenosine Alternative Splicing Antineoplastic Agents Basic Science Biology Cell physiology Cells Cervical Clinical Trials Complex DNA Damage Data Deposition Environment Enzymes Epithelium Event Exclusion Exons Future Gene Expression Genetic Transcription Genome Genomic approach Head and Neck Cancer Human Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papilloma virus infection Human papillomavirus 18 Incidence Infection Introns Knowledge Life Cycle Stages Link Malignant Neoplasms Malignant neoplasm of cervix uteri Maps Messenger RNA Methylation Methyltransferase Modification Molecular Target Papillomavirus Pattern Phase Phenotype Play Poly(A)+ RNA Polyadenylation Positioning Attribute Protein Inhibition Protein-Arginine N-Methyltransferase Proteins RNA Splicing Regulation Risk Factors Role Sexually Transmitted Diseases Site Site-Directed Mutagenesis Technology Testing Tissues Transcript Viral Viral Gene Expression Regulation Viral Genes Viral Genome Viral Proteins Virus Virus Diseases Virus Replication Work chronic infection cis acting element drug development druggable target histone methylation human papilloma virus oncogene inhibitor keratinocyte differentiation novel therapeutics pre-clinical recruit response tumor viral DNA viral RNA

项目摘要

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.

人乳头瘤病毒（HPV）感染是最常见的性传播在美国感染。这些感染导致全世界估计有5％的癌症。 HPV感染了分化上皮组织的基础角质形成细胞。重要的是，只有持久 HPV感染导致癌症。因此，了解病毒宿主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。我们使用了单细胞基因组学方法来鉴定蛋白精氨酸N-甲基转移酶1 （PRMT1）是原发性人宫颈内病毒感染持续性的重要因素细胞。我们证明PRMT1抑制增加了HPV18上M6A标记的沉积病毒mRNA，特别针对内含子区域，导致病毒的总体失调基因。我们假设PRMT1调节病毒mRNA的RBM15控制M6A沉积调节持续感染期间的替代剪接。 PRMT最近出现了用于抗癌药物开发的分子靶标。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。该项目的基础研究确定PRMT抑制剂是否可以转化用于HPV感染和肿瘤。