RNA Splicing Control in Rous Sarcoma Virus

劳斯肉瘤病毒中的 RNA 剪接控制

• 批准号: 7895522
• 负责人: MARK T MCNALLY
• 金额: $ 27.91万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-14 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895522
• 关键词: 3' Splice Site; Adaptor Signaling Protein; Adenoviruses; Alternative Splicing; Animals; Binding; Binding Proteins; Biological Assay; Birds; Cell physiology; Cells; Coupled; Couples; Coupling; Development; Educational process of instructing; Elements; Ensure; Exons; Failure; Genome; Genomics; Immunodeficiency and Cancer; In Vitro; Integration Host Factors; Investigation; Lead; Length; Life Cycle Stages; Link; Malignant Neoplasms; Messenger RNA; Modeling; Oncogene Activation; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Play; Poly A; Polyadenylation; Process; Protein Binding Domain; Protein Family; Proteins; Proto-Oncogenes; Publishing; RNA; RNA Processing; RNA Recognition Motif; RNA Splicing; Reading; Recruitment Activity; Regulation; Reporting; Retroviridae; Role; Rous sarcoma virus; Simian virus 40; Site; Small Nuclear Ribonucleoproteins; Study models; System; Therapeutic; Time; Trans-Activators; Transcript; U1 Small Nuclear Ribonucleoprotein; Viral; Virion; Virus; Virus Replication; Work; base; design; hnRNP-F; hnRNP-H; human disease; in vivo; insight; mRNA Precursor; novel; novel therapeutics; pathogen; protein protein interaction; public health relevance; research study; src Genes; tool; viral RNA; virus host interaction

DESCRIPTION (provided by applicant): Characterizing unique virus-host interactions is key to understanding pathogenesis and developing therapeutics to block the virus life cycle. Because of their intimate associations with host cells, viruses have also been exploited as tools for studying many basic cellular processes, including RNA processing. For retroviruses, control of splicing and polyadenylation are important aspects of the replication cycle. Splicing of retroviral primary transcripts must be controlled since high levels of unspliced RNA are needed as mRNA, and for incorporation as genomes into progeny virions. Polyadenylation control is important because failure to use the viral polyadenylation site results in read-through transcripts that extend into downstream genomic sequences; this is the basis for oncogenic transformation and the ability of retroviruses to acquire host cell sequences through oncogene capture. We are studying viral cis elements and host trans-acting factors required for proper RNA processing and replication of Rous sarcoma virus (RSV); paradigms established for RSV RNA processing control will provide insights into host cell RNA processing regulation. Our work focuses in part on a novel RNA processing control element, the negative regulator of splicing (NRS), that contributes to the accumulation of genome-length RNA by acting as a pseudo 5'ss to repress splicing. We will continue investigation of factors required for novel snRNP interactions with the NRS and their role in splicing control. Splicing and polyadenylation are coupled in the cells that RSV infects, raising the question of how viral RNAs are efficiently polyadenylated. We will continue examining a novel coupling mechanism whereby the NRS, in addition to splicing control, ensures the proper polyadenylation of genome-length RNA that do not benefit from splicing. RSV also harbors a site-specific splicing regulator, the suppressor of src splicing (SSS), that controls src splicing and is required for proper replication. We will identify host factors required for SSS activity and explore the mechanism by which it blocks splicing. Through this work we will enhance our understanding of control of critical RNA processing steps required for viral replication and pathogenesis, and could lead to new therapeutics designed to block replication. The RSV system also provides a powerful tool to dissect novel cellular mechanisms of RNA processing regulation. PUBLIC HEALTH RELEVANCE: Retroviruses are major animal pathogens that cause considerable human disease, including immunodeficiencies and cancer. Viral replication requires unconventional use of the machines inside cells that make viral RNA. Understanding how these agents interact with manipulate the host cell RNA processing machinery could lead to new therapeutics designed to block replication and teach us novel ways in which the host machines work.

描述（由申请人提供）：表征独特的病毒-宿主相互作用是理解发病机制和开发阻断病毒生命周期的治疗方法的关键。由于它们与宿主细胞的密切联系，病毒也被用作研究许多基本细胞过程的工具，包括RNA加工。对于逆转录病毒，剪接和多聚腺苷酸化的控制是复制周期的重要方面。逆转录病毒初级转录物的剪接必须受到控制，因为需要高水平的未剪接RNA作为mRNA，并作为基因组掺入后代病毒体中。多聚腺苷酸化控制是重要的，因为未能使用病毒多聚腺苷酸化位点导致延伸到下游基因组序列的通读转录本;这是致癌转化和逆转录病毒通过癌基因捕获获得宿主细胞序列的能力的基础。我们正在研究Rous肉瘤病毒（RSV）的正确RNA加工和复制所需的病毒顺式元件和宿主反式作用因子;为RSV RNA加工控制建立的范例将为宿主细胞RNA加工调节提供见解。我们的工作部分集中在一个新的RNA加工控制元件，剪接的负调节因子（NRS），有助于积累的基因组长度的RNA作为一个假5 'ss抑制剪接。我们将继续研究新snRNP与NRS相互作用所需的因素及其在剪接控制中的作用。RSV感染的细胞中剪接和多聚腺苷酸化偶联，引发了病毒RNA如何有效多聚腺苷酸化的问题。我们将继续研究一种新的偶联机制，其中NRS，除了剪接控制，确保适当的多聚腺苷酸化的基因组长度的RNA，不受益于剪接。RSV还具有位点特异性剪接调节因子，src剪接抑制因子（SSS），其控制src剪接并且是正确复制所需的。我们将确定SSS活动所需的宿主因子，并探索其阻断剪接的机制。通过这项工作，我们将提高我们对病毒复制和发病机制所需的关键RNA加工步骤的控制的理解，并可能导致旨在阻断复制的新疗法。RSV系统还提供了一个强大的工具来剖析RNA加工调节的新细胞机制。公共卫生相关性：逆转录病毒是主要的动物病原体，可引起相当多的人类疾病，包括免疫缺陷和癌症。病毒复制需要非常规地使用细胞内制造病毒RNA的机器。了解这些药物如何相互作用，操纵宿主细胞RNA加工机制，可能会导致新的治疗方法，旨在阻止复制，并教会我们宿主机器工作的新方式。