Functional characterization of proteins associated with promeylocytic leukemia nuclear bodies

真核细胞的绝大多数遗传物质存在于细胞核中，细胞核是一个高度分隔的细胞器。细胞核内有许多亚核区室，它们不一定是遗传物质的避难所，但却作为调节涉及遗传物质的各种核过程的重要中心。这些亚核区室之一被称为早幼粒细胞白血病（PML）核体，其在诱导细胞凋亡和细胞衰老、抑制增殖、维持基因组稳定性和抗病毒应答的调节中发挥重要作用。已经发现超过100种蛋白质永久或短暂地存在于PML体内，然而，它们与这种细胞器的关联的性质、它们彼此之间的相互作用以及它们如何有助于调节各种细胞过程仍然在很大程度上未被表征。拟议研究计划的长期目标旨在阐明PML机构通过全面了解其相关蛋白质的功能来调节各种核过程的机制。 发现PML小体与锌指蛋白827（ZNF 827）相互作用，锌指蛋白827是一种与细胞存活有关的特征不明显的蛋白质。ZNF 827含有9个锌指基序，在体内被发现是SUMO化的。在接下来的五年里，我们计划确定ZNF 827和PML体之间的生物化学和遗传相互作用。具体而言，我们的短期目标是：（1）表征ZNF 827与PML小体的结合性质以及其在应激诱导的细胞死亡调节中的作用，（2）确定翻译后修饰（如SUMO化）是否调节ZNF 827与PML小体的相互作用，以及（3）确定锌指基序调节ZNF 827与PML小体相互作用的机制。我们希望这项拟议的研究计划将为我们理解PML小体如何与其相关蛋白质进行通信以调节应激诱导的细胞死亡提供新的思路。拟议的研究将进一步为我们探索新的相互作用提供基础。它也将成为我们探索和操纵PML体控制各种细胞过程的最终目标的基础。从这项拟议的研究计划中获得的知识，预计将显着提高我们的基本过程的细胞存活和增殖，一个领域高度相关的药物发现，生物技术和制药工业的知识。

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.