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Cancers 2014, 6(3), 1464-1486; doi:10.3390/cancers6031464

Phosphorylation of Large T Antigen Regulates Merkel Cell Polyomavirus Replication

1
Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
2
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
*
Author to whom correspondence should be addressed.
Received: 18 February 2014 / Revised: 18 June 2014 / Accepted: 24 June 2014 / Published: 8 July 2014
(This article belongs to the Special Issue Merkel Cell Carcinoma)
View Full-Text   |   Download PDF [993 KB, 11 July 2014; original version 8 July 2014]   |  

Abstract

Merkel Cell Polyomavirus (MCPyV) was recently discovered as a novel human polyomavirus that is associated with ~80% of Merkel Cell Carcinomas. The Large Tumor antigen (LT) is an early viral protein which has a variety of functions, including manipulation of the cell cycle and initiating viral DNA replication. Phosphorylation plays a critical regulatory role for polyomavirus LT proteins, but no investigation of MCPyV LT phosphorylation has been performed to date. In this report mass spectrometry analysis reveals three unique phosphorylation sites: T271, T297 and T299. In vivo replication assays confirm that phosphorylation of T271 does not play a role in viral replication, while modification at T297 and T299 have dramatic and opposing effects on LT’s ability to initiate replication from the viral origin. We test these mutants for their ability to bind, unwind, and act as a functional helicase at the viral origin. These studies provide a framework for understanding how phosphorylation of LT may dynamically regulate viral replication. Although the natural host cell of MCPyV has not yet been established, this work provides a foundation for understanding how LT activity is regulated and provides tools for better exploring this regulation in both natural host cells and Merkel cells. View Full-Text
Keywords: MCPyV; Large T antigen; polyomavirus replication; phosphorylation MCPyV; Large T antigen; polyomavirus replication; phosphorylation
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Diaz, J.; Wang, X.; Tsang, S.H.; Jiao, J.; You, J. Phosphorylation of Large T Antigen Regulates Merkel Cell Polyomavirus Replication. Cancers 2014, 6, 1464-1486.

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