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The role of asymmetric protein dimethylation during the human papillomavirus lifecycle

不对称蛋白质二甲基化在人乳头瘤病毒生命周期中的作用

基本信息

批准号：
10518761
负责人：
Koenraad Van Doorslaer
金额：
$ 38.05万
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：
2022-06-07 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518761
关键词：
3-Dimensional Address Affect Alternative Splicing Anogenital cancer Biological Assay Biology Cell physiology Cells Cervical Chromosomes Clinical Trials Complex DNA Damage Data Deposition Development Environment Enzymes Epithelial Event Exons Genome Genomic approach Head and Neck Cancer Head and neck structure Histones Human Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papilloma virus infection Human papillomavirus 18 Incidence Infection Introns Knowledge Lead Length Link Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Messenger RNA Methylation Methyltransferase Modification Papillomavirus Pattern Phase Phenotype Play Polyadenylation Primary Infection Production Protein Inhibition Protein Overexpression Protein-Arginine N-Methyltransferase Proteins RNA RNA Splicing RNA methylation Regulation Risk Factors Role Sexually Transmitted Diseases Site Testing Tissues Transcript Viral Viral Genes Viral Genome Viral Proteins Virus Virus Diseases Virus Replication Work acute infection chronic infection druggable target human papilloma virus oncogene keratinocyte differentiation novel therapeutics single-cell RNA sequencing spatiotemporal tool transcriptome viral DNA

项目摘要

Infections with human papillomaviruses (HPVs) are the most common sexually transmitted infection in the US. In addition to causing cervical and other anogenital cancers and a rising incidence of head and neck cancer, HPVs are responsible for an estimated 5% of cancers worldwide. Importantly, persistent infection, and not an acute infection is the primary risk factor for (cervical) cancer development. Thus, understanding the virus-host interplay that promotes or restrict viral persistence has important implications for HPV biology and human cancers. Until recently, it has been challenging to study the immediate early events of the HPV lifecycle following infection and how these events contribute to initial genome amplification during the establishment phase and long-term viral persistence. We used a single-cell genomics approach to identify cellular factors involved in viral infection and persistence. Our preliminary data identify protein arginine N-methyltransferase 1 (PRMT1) as an important factor upon viral infection of primary human cervical cells. PRMT1 regulates several cellular functions that may be relevant to the HPV lifecycle. We demonstrate that PRMT1 inhibition leads to a highly dysregulated splicing pattern of the viral genes. Mechanistically, we identify a dramatic increase in m6A modifications of viral mRNA, specifically in introns. These data implicate RBM15, a regulatory subunit of the m6A methyltransferase complex. We hypothesize that PRMT1 regulates RBM15 controlled m6a deposition on viral mRNA to temporally regulate alternative splicing throughout viral infection. We will (1) Determine the importance of asymmetric protein dimethylation throughout the viral lifecycle. (2) Determine the role for RBM15 in the PRMT1 mediated regulation of m6a methylation of viral mRNA. (3) Determine the effects of m6a methylation on viral mRNA splicing. PRMT1 inhibition leads to dysregulated viral splicing. This proposal addresses a critical gap in our knowledge relating to how HPV splicing is regulated for optimal infection, establishment, and long-term persistence. We identify PRMT1 as a regulator of viral splicing and hypothesize that this occurs through targeted m6A deposition on viral introns. Since PRMT1 is an established druggable target, these results may lead to novel therapeutics for HPV-induced cancers.

人乳头瘤病毒（HPV）感染是美国最常见的性传播感染。除了引起宫颈癌和其他肛门生殖器癌以及头颈癌发病率的上升外，HPV还导致全球约5%的癌症。重要的是，持续感染，而不是急性感染是（宫颈）癌发展的主要风险因素。因此，了解促进或限制病毒持久性的病毒-宿主相互作用对HPV生物学和人类癌症具有重要意义。直到最近，研究感染后HPV生命周期的立即早期事件以及这些事件如何在建立阶段和长期病毒持续性期间促进初始基因组扩增一直具有挑战性。我们使用单细胞基因组学方法来确定参与病毒感染和持久性的细胞因子。我们的初步数据确定蛋白质精氨酸N-甲基转移酶1（PRMT 1）作为病毒感染原代人宫颈细胞的重要因素。PRMT 1调节可能与HPV生命周期相关的几种细胞功能。我们证明PRMT 1抑制导致病毒基因的高度失调的剪接模式。从机制上讲，我们发现病毒mRNA的m6 A修饰显著增加，特别是在内含子中。这些数据涉及RBM 15，m6 A甲基转移酶复合物的调节亚基。我们假设PRMT 1调节RBM 15控制的m6 a在病毒mRNA上的沉积，从而在整个病毒感染过程中暂时调节可变剪接。我们将（1）确定在整个病毒生命周期中蛋白质不对称二甲基化的重要性。(2)确定RBM 15在PRMT 1介导的病毒mRNA的m6 a甲基化调节中的作用。(3)确定m6 a甲基化对病毒mRNA剪接的影响。PRMT 1抑制导致病毒剪接失调。该提案解决了我们知识中的一个关键空白，即如何调节HPV剪接以实现最佳感染，建立和长期持续性。我们确定PRMT 1作为病毒剪接的调节因子，并假设这是通过靶向m6 A沉积在病毒内含子上而发生的。由于PRMT 1是一个确定的可药物靶点，这些结果可能会导致HPV诱导的癌症的新疗法。