Functional characterization of proteins associated with promeylocytic leukemia nuclear bodies

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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.