Large T Antigens of Polyomaviruses: Amazing Molecular Machines

Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
Annual review of microbiology (Impact Factor: 12.18). 10/2012; 66(1):213-36. DOI: 10.1146/annurev-micro-092611-150154
Source: PubMed


The large tumor antigen (T antigen) encoded by simian virus 40 is an amazing molecular machine because it orchestrates viral infection by modulating multiple fundamental viral and cellular processes. T antigen is required for viral DNA replication, transcription, and virion assembly. In addition, T antigen targets multiple cellular pathways, including those that regulate cell proliferation, cell death, and the inflammatory response. Ectopic T antigen expression results in the immortalization and transformation of many cell types in culture and T antigen induces neoplasia when expressed in rodents. The analysis of the mechanisms by which T antigen carries out its many functions has proved to be a powerful way of gaining insights into cell biology. The accelerating pace at which new polyomaviruses are being discovered provides a collection of novel T antigens that, like simian virus 40, can be used to discover and study key cellular regulatory systems.

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    • "Taken together, PyVs may impede the repair of host genotoxic stress that accumulates during infection. The above stated model is contrasted, however, by the observation that BKPyV infection of primary renal proximal tubule epithelial cells in the absence of ATM and ATR DDRs leads to the formation of fragmented nuclei in a proportion of infected cells (Jiang et al., 2012). "
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    ABSTRACT: Viruses are obligate intracellular parasites that subvert cellular metabolism and pathways to mediate their own replication-normally at the expense of the host cell. Polyomaviruses are a group of small DNA viruses, which have long been studied as a model for eukaryotic DNA replication. Polyomaviruses manipulate host replication proteins, as well as proteins involved in DNA maintenance and repair, to serve as essential cofactors for productive infection. Moreover, evidence suggests that polyomavirus infection poses a unique genotoxic threat to the host cell. In response to any source of DNA damage, cells must initiate an effective DNA damage response (DDR) to maintain genomic integrity, wherein two protein kinases, ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), are major regulators of DNA damage recognition and repair. Recent investigation suggests that these essential DDR proteins are required for productive polyomavirus infection. This review will focus on polyomaviruses and their interaction with ATMand ATR-mediated DNA damage responses and the effect of this interaction on host genomic stability.
    Virologica Sinica 04/2015; 30(2). DOI:10.1007/s12250-015-3583-6
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    • "Why this distribution exists within the glioma cell population is also unknown. Detecting JCV DNA replication in Hs 683 and U87 cells will likely depend upon increasing the percentage of glioma cells that have JCV T-ag in their nuclei (Broekema and Imperiale, 2012). Nevertheless, since JCV T-ag is known to accumulate in the nuclei of glial cells derived from PML patients (Stoner et al., 1986), it is concluded that Hs 683 and U87 cells are not ideal models for additional studies of this disease. "
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    ABSTRACT: Progressive Multifocal Leukoencephalopathy (PML) is caused by lytic replication of JC virus (JCV) in specific cells of the central nervous system. Like other polyomaviruses, JCV encodes a large T-antigen helicase needed for replication of the viral DNA. Here, we report the development of a luciferase-based, quantitative and high-throughput assay of JCV DNA replication in C33A cells, which, unlike the glial cell lines Hs 683 and U87, accumulate high levels of nuclear T-ag needed for robust replication. Using this assay, we investigated the requirement for different domains of T-ag, and for specific sequences within and flanking the viral origin, in JCV DNA replication. Beyond providing validation of the assay, these studies revealed an important stimulatory role of the transcription factor NF1 in JCV DNA replication. Finally, we show that the assay can be used for inhibitor testing, highlighting its value for the identification of antiviral drugs targeting JCV DNA replication.
    Virology 11/2014; s 468–470:113–125. DOI:10.1016/j.virol.2014.07.042 · 3.32 Impact Factor
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    • "Cells infected with wild-type SV40 are less susceptible to cytotoxic T cells and produce lower levels of cytokines compared to cell infected with an SV40 mutant unable to express miRNA. The miRNA-mediated reduction of LT-ag expression may be a strategy of the virus to evade the immune system and to persist in its host (Chen et al., 2013; Sullivan et al., 2005; You et al., 2012). Several other human and non-human polyomaviruses have been shown to encode miRNAs, including the NHP polyomavirus SA12 (Cantalupo et al., 2005; Lagatie et al., 2013). "
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    ABSTRACT: Polyomaviruses have so far only been isolated from mammals and birds. Typical for all members of this family is their double-stranded genome of approximately 5,000 base-pairs which can be divided into an early region encoding at least two functional proteins, the large and small tumor antigens, and a late region encompassing genes for the capsid proteins VP1 and VP2. During the last 10 years several novel polyomaviruses have been described in non-human primates and man. This review compares the non-human primate polyomavirus genomes that have been completely sequenced with each other and with the genomes of human polyomaviruses. We predict the presence of protein- and microRNA-encoding sequences. Our analyses demonstrate that several genetically distinct groups of non-human primate polyomaviruses exist, that different polyomaviruses can infect the same non-human primate species but that most of their proteins display highly similar domains and motifs, indicating conservation of key functions.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 06/2014; 26. DOI:10.1016/j.meegid.2014.05.030 · 3.02 Impact Factor
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