Polyoma virus will continue to serve as a model system to study the synthesis and processing of mammalian RNA molecules. The applicant plans to perform a number of studies designed to understand the switch from mostly early-strand mRNAs before the initiation of viral DNA synthesis to mostly late-strand mRNAs afterwards. The regulation of both early and late strand RNA levels is not at the promoter level, and is post-transcriptional. Late-strand RNA levels are regulated in an unexpected way-they appear to positively influence their own accumulation during infection. He will determine what sequences are critical for the activation of late gene expression after DNA replication initiation. The regulation of early-strand gene expression by a novel mechanism (nuclear antisense RNA from the late strand) that is likely to be generally used by cells to regulate the expression of many of their own genes. This virus provides a powerful genetic and biochemical system in which to study antisense regulation and to learn how to exploit this knowledge to regulate the expression of other genes, both viral and cellular. He has shown that, in the presence of late-strand antisense molecules, many nuclear early-strand RNAs are modified by the enzyme double strand RNA adenosine deaminase (ADAR1). This appears to be a major aspect of the downregulation of early gene expression at late times in the viral life cycle. Edited RNAs are retained in the nucleus. He will use a variety of approaches to learn more about the nuclear retention of inosine-containing RNAs, and will investigate the role of ADAR1 in polyoma infection, and the influence of infection on ADAR1 expression, activity, and localization.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA045382-14
Application #
6095264
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1987-07-01
Project End
2005-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
14
Fiscal Year
2000
Total Cost
$305,231
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Carmichael, Gordon G (2016) Gene Regulation and Quality Control in Murine Polyomavirus Infection. Viruses 8:
Garren, Seth B; Kondaveeti, Yuvabharath; Duff, Michael O et al. (2015) Global Analysis of Mouse Polyomavirus Infection Reveals Dynamic Regulation of Viral and Host Gene Expression and Promiscuous Viral RNA Editing. PLoS Pathog 11:e1005166
Carmichael, Gordon (2015) My RNA world: past, present and future. RNA 21:578-9
Yang, Li; Duff, Michael O; Graveley, Brenton R et al. (2011) Genomewide characterization of non-polyadenylated RNAs. Genome Biol 12:R16
Chen, Ling-Ling; Carmichael, Gordon G (2010) Decoding the function of nuclear long non-coding RNAs. Curr Opin Cell Biol 22:357-64
Huang, Yingqun; Carmichael, Gordon G (2009) RNA processing in the polyoma virus life cycle. Front Biosci (Landmark Ed) 14:4968-77
Chen, Ling-Ling; Carmichael, Gordon G (2009) Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. Mol Cell 35:467-78
Gu, Rui; Zhang, Zuo; DeCerbo, Joshua N et al. (2009) Gene regulation by sense-antisense overlap of polyadenylation signals. RNA 15:1154-63
Gu, R; Zhang, Z; Carmichael, G G (2006) How a small DNA virus uses dsRNA but not RNAi to regulate its life cycle. Cold Spring Harb Symp Quant Biol 71:293-9
Wang, Qiaoqiao; Zhang, Zuo; Blackwell, Katherine et al. (2005) Vigilins bind to promiscuously A-to-I-edited RNAs and are involved in the formation of heterochromatin. Curr Biol 15:384-91

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