Investigating chromatin control by an Adenovirus histone-like protein

 描述（由申请方提供）：病毒是专性细胞内寄生虫，其依赖于模仿细胞蛋白质的结构和功能的能力，以将细胞重定向至病毒产生。在这个建议中，我专注于一种来自腺病毒的病毒蛋白，称为蛋白VII，其序列与细胞组蛋白高度相似。我认为这种病毒组蛋白样蛋白通过模仿组蛋白和操纵细胞染色质来促进病毒生长。当蛋白VII在20世纪70年代末首次被描述为基于一级序列的组蛋白样时，对组蛋白的作用几乎没有了解。从那时起，在表观遗传学领域，人们越来越重视组蛋白上保守的位点特异性翻译后修饰（PTM）及其对细胞过程的影响。腺病毒的双链DNA基因组与组蛋白样蛋白VII包装在病毒粒子中。我的初步结果表明，核蛋白VII足以改变细胞染色质， 下调照射后的DNA损伤反应（DDR）。我还发现，蛋白质VII被修改类似于组蛋白PTM，这可能涉及染色质变化或DDR下调的机制。蛋白VII PTM还可用于破坏细胞组蛋白PTM并改变抗病毒基因的转录以促进病毒复制。的目的 一项计划是确定蛋白VII在细胞染色质中的功能，以及这些功能如何使病毒 复制的我建议利用目前的知识组蛋白作为一个框架，通过三个具体的目标来研究蛋白VII的功能：1）确定蛋白VII对细胞染色质结构的影响，2）确定蛋白VII对DNA损伤反应的影响，3）确定蛋白VII对转录的影响。这项研究的结果将为确定病毒感染期间发生的染色质变化提供基础。这是第一次发现组蛋白样蛋白改变细胞染色质或影响一个重要的细胞途径。该项目将是对表观遗传学领域的独特贡献，因为它是在内源性细胞组蛋白PTM和细胞DDR的背景下首次研究病毒组蛋白样蛋白的功能。

 DESCRIPTION (provided by applicant): 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.