Functional characterization of proteins associated with promeylocytic leukemia nuclear bodies

早幼粒细胞白血病核体相关蛋白的功能表征

• 批准号: RGPIN-2016-05110
• 负责人: Zhu, XuDong
• 金额: $ 2.26万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=669901
• 关键词: Functional; characterization; proteins; associated; promeylocytic

The vast majority of the genetic material of the eukaryotic cell resides in the nucleus, which is a highly compartmentalized organelle. Within the nucleus are a variety of subnuclear compartments that do not necessarily harbour the genetic material but serve as important centers for regulating a variety of nuclear processes involving the genetic material. One of these subnuclear compartments is known as promyelocytic leukemia (PML) nuclear bodies, which play an important role in the regulation of induction of apoptosis and cellular senescence, inhibition of proliferation, maintenance of genomic stability and the antiviral response. Over 100 proteins have been found to reside, permanently or transiently, in PML bodies, however, the nature of their association with this organelle, their interactions with one another, and how they contribute to the regulation of various cellular processes remains largely uncharacterized. The long-term objective of the proposed research program aims to elucidate the mechanism by which PML bodies regulate a diverse range of nuclear processes through a comprehensive understanding of the function of their associated proteins. *** PML bodies are found to interact with zinc finger protein 827 (ZNF827), a poorly characterized protein implicated in cell survival. ZNF827 contains nine zinc finger motifs and are found to be SUMOylated in vivo. Over the next five years, we plan to define biochemical and genetic interactions between ZNF827 and PML bodies. Specifically, our short-term objectives are to: (1) characterize the nature of ZNF827 association with PML bodies as well as its role in the regulation of stress-induced cell death, (2) determine if post-translational modification such as SUMOylation regulates ZNF827 interaction with PML bodies and (3) determine the mechanism by which zinc finger motifs regulate ZNF827 interaction with PML bodies. We expect that this proposed research program will shed new light into our understanding of how PML bodies communicate with their associated proteins to regulate stress-induced cell death. The proposed research will further provide the foundation from which we can probe for novel interactions. It will also form the basis for our ultimate goal of exploration and manipulation of PML bodies in the control of various cellular processes. Knowledge gained from this proposed research program is expected to significantly enhance our knowledge of fundamental processes underlying cell survival and proliferation, an area highly relevant to drug discovery, biotechnology and pharmaceutical industry. **

真核细胞的绝大多数遗传物质存在于细胞核中，这是一个高度区隔的细胞器。在细胞核内有各种各样的亚核室，它们不一定容纳遗传物质，但作为调节涉及遗传物质的各种核过程的重要中心。其中一种亚核室被称为早幼粒细胞白血病（PML）核小体，它在诱导凋亡和细胞衰老、抑制增殖、维持基因组稳定性和抗病毒反应等方面发挥重要作用。超过100种蛋白质已被发现永久或短暂地驻留在PML体中，然而，它们与该细胞器的关联性质，它们之间的相互作用以及它们如何促进各种细胞过程的调节在很大程度上仍未被表征。该研究计划的长期目标是通过对PML相关蛋白功能的全面了解，阐明PML小体调节多种核过程的机制。***发现PML小体与锌指蛋白827 （ZNF827）相互作用，锌指蛋白是一种与细胞存活有关的不太明确的蛋白。ZNF827含有9个锌指基序，在体内被发现被summoylated。在接下来的五年里，我们计划确定ZNF827和PML小体之间的生化和遗传相互作用。具体而言，我们的短期目标是：(1)表征ZNF827与PML小体关联的性质及其在调节应激诱导细胞死亡中的作用；(2)确定SUMOylation等翻译后修饰是否调节ZNF827与PML小体的相互作用；(3)确定锌指基序调节ZNF827与PML小体相互作用的机制。我们期望这项研究计划将为我们理解PML体如何与其相关蛋白沟通以调节应激诱导的细胞死亡提供新的思路。所提出的研究将进一步为我们探索新的相互作用提供基础。这也将为我们探索和操纵PML体控制各种细胞过程的最终目标奠定基础。从这个拟议的研究项目中获得的知识有望显著提高我们对细胞存活和增殖基本过程的认识，这是一个与药物发现、生物技术和制药工业高度相关的领域。**