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，这是一个高度区隔的细胞器。在细胞核内有各种亚核隔间，它们不一定藏匿遗传物质，但充当调节涉及遗传物质的各种核过程的重要中心。其中一个亚核室称为早幼粒细胞白血病(PML)核体，它在诱导细胞凋亡和细胞衰老、抑制增殖、维持基因组稳定和抗病毒反应中发挥着重要作用。超过100种蛋白质被发现永久或短暂地存在于PML小体中，然而，它们与这个细胞器的结合的性质，它们彼此之间的相互作用，以及它们如何参与调节各种细胞过程，在很大程度上仍不清楚。拟议研究计划的长期目标旨在通过全面了解PML相关蛋白质的功能来阐明PML小体调节各种核过程的机制。*PML小体被发现与锌指蛋白827(ZNF827)相互作用，ZNF827是一种与细胞生存有关的特征不佳的蛋白质。ZNF827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，我们计划定义ZNF827和PML小体之间的生化和遗传相互作用。具体地说，我们的短期目标是：(1)表征ZNF827与PML小体相互作用的性质及其在调节应激诱导的细胞死亡中的作用；(2)确定翻译后修饰(如SUMO化)是否调节ZNF827与PML小体的相互作用；(3)确定锌指基序调控ZNF827与PML小体相互作用的机制。我们期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沟通以调节应激诱导的细胞死亡提供新的线索。这项拟议的研究将进一步为我们探索新的相互作用提供基础。这也将成为我们探索和操纵PML小体以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著增强我们对细胞生存和增殖基本过程的了解，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。**

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. **