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.
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.
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