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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    • "Large T antigen (LTag) contains four conserved domains, the J domain, the origin-binding domain (OBD), the zinc-binding domain, and the AAA+ ATPase domains. The J domain may have a role in viral DNA replication, OBD may contribute to DNA replication and binding to transcription factors, and ATPase has enzymatic activities to support the required energy, while the zinc finger domain is responsible for the oligomerization of LTag forming hexamers[106,187]. "

    Full-text · Article · Jan 2016
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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.
    Preview · Article · Apr 2015 · Virologica Sinica
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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.
    Full-text · Article · Nov 2014 · Virology
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