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疾病在美国感染。据估计，全球 5% 的癌症都是由这些感染引起的。 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来鉴定蛋白质精氨酸 N-甲基转移酶 1 (PRMT1) 作为原发性人类宫颈病毒感染持续存在的重要因素细胞。我们证明 PRMT1 抑制会增加 HPV18 上 m6A 标记的沉积病毒 mRNA，特别是内含子区域，导致病毒剪接整体失调基因。我们假设 PRMT1 调节 RBM15 控制的 m6a 在病毒 mRNA 上的沉积调节持续感染期间的选择性剪接。 PRMT 最近出现为抗癌药物开发的分子靶点。尽管许多候选人仍处于临床前阶段，部分抑制剂已进入临床试验。本项目的基础研究确定 PRMT 抑制剂是否可以转化用于 HPV 感染和肿瘤。