Archives—September 2010

RNA Splicing and Polyadenylation Control in Retroviruses: Implications for Cellular Control

September 3, 2010

U113 M&M

2:00 – 3:00 pm

Presenter: Dr. Mark McNally, Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee

Abstract: 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 is an important aspect 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), not only to further an understanding of virus replication but to 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 continue to study a host factor, hnRNP H, that is required for high-efficiency binding of U11 snRNP (a splicing factor in the ‘minor’ splicing pathway that binds to 5′ splice sites) to the NRS, with an eye towards deeper understanding of its role in alternative splicing of cellular genes. Interestingly, the NRS is also required for proper polyadenylation of viral RNAs, and we have made the novel finding that a class of splicing factors (SR proteins) mediates stimulation of polyadenylation by the NRS in a position-dependent manner; this observation suggests that some cellular mRNAs might use a similar mechanism of polyadenylation control. Thus, the RSV system has provided a powerful tool to dissect novel cellular mechanisms of RNA processing regulation.