Polyoma virus will continue to serve as a model system to study RNA metabolism in mammalian cells. We will 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 focus will be on RNA editing. We have found that the regulation of both early and late strand RNA levels is post-transcriptional, and late-strand RNA levels are regulated in an unexpected way: polyadenylation is inefficient at late times, leading to mRNAs that accumulate because they can be spliced more efficiently. We recently discovered that this regulation appears to involve editing of the late poly(A) signal, and we propose to follow up these observations with a number of studies to examine how this occurs. In related work we have found that the regulation of early-strand gene expression is by nuclear antisense RNA, which is likely to be generally used by cells to regulate the expression of many of their own genes. This virus thus 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. We have shown that in the presence of late-strand antisense molecules, many nuclear early-strand RNAs are edited by the enzyme ADAR1. Further, we have discovered that there appear to be two nuclear responses to dsRNAs that have been extensively edited by this enzyme. First, a complex of three proteins (p54nrb, PSF and matrin 3) can bind cooperatively to promiscuously edited RNAs and prevent their export to the cytoplasm. Second, the protein vigilin binds to edited RNAs and can lead to the establishment of heterochromatic gene silencing through a novel pathway that involves components of the cellular DNA repair machinery. We propose to examine each of these newly-discovered response pathways in more detail, and especially in the context of polyoma infection.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Blair, Donald G
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University of Connecticut
Schools of Medicine
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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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