Viruses are obligate intracellular parasites that rely on the ability to mimic the structure and function of cellular proteins to redirect the cell towards vral production. In this proposal, I focus on a viral protein from Adenovirus called protein VII whose sequence is highly similar to cellular histone proteins. I propose that this viral histone-like protein facilitates viral growth by mimicking histones and manipulating cellular chromatin. When protein VII was first described as histone-like based on primary sequence in the late 1970s, there was little understanding of the role of histone proteins. Since then, in the field of epigenetics has led to an increased appreciation for conserved site-specific post-translational modifications (PTMs) on histone proteins and their impact on cellular processes. The double-stranded DNA genome of Adenovirus is packaged in the virion with histone-like protein VII. My preliminary results show that nuclear protein VII is sufficient to alter cellular chromatin and can down-regulate the DNA damage response (DDR) upon irradiation. I also find that protein VII is modified analogously to histone PTMs, which may be involved in the mechanism of chromatin change or DDR down-regulation. Protein VII PTMs may also serve to disrupt cellular histone PTMs and alter transcription of antiviral genes to promote viral replication. The objective of this proposal is to determine functions of protein VII at cellular chromatin and how these benefit viral replication. I propose to utilize current knowledge of histones as a framework to investigate protein VII function through three specific aims: 1) to define the impact of protein VII on cellula chromatin structure, 2) to define the impact of protein VII on the DNA damage response, and 3) to determine the effect of protein VII on transcription. The outcome of this research will provide a basis for defining the chromatin changes that take place during viral infection. This is the firs time that a histone-like protein has been found to alter cellular chromatin or effect an essential cellular pathway. This project will be a unique contribution to the field of epigenetics as it is te first investigation into the function of a viral histone-like protein in the context of endogenous cellular histone PTMs and the cellular DDR.
Cellular proteins called histones control access to the genome by tightly binding DNA in a structure known as chromatin. Adenoviruses, which cause upper respiratory infections in children and the immuno-compromised, rely on the ability to mimic cellular proteins to hijack the cell for viral production. One Adenoviral protein, called protein VII, remarkably mimics cellular histones and the proposed study will examine how this histone-like protein disrupts chromatin and contributes to viral production.
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