Characterization of a Potential Nuclear Protein Depot

Wistar Institute, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Specific nuclear domains named ND10, PML bodies or PODs have reached prominence because proteins contained in these structures are directly or indirectly associated with specific diseases such as acute promyelocytic leukemia, various viral infections, cadmium and arsenic exposure and other environmental toxins. In addition, cellular regulatory loops induced by interferon and thermal stress are correlated with recruitment to or release of regulatory proteins like PML, Daxx and Sp100 from ND10 However, none of the encompassing transcriptional changes appear to occur directly at these nuclear sites. We therefore hypothesize that ND 10 function as nuclear depots, thus separating the functional site of the ND 10-associated proteins from that of their highest aggregation at ND 10. To determine what functions are controlled through release or recruitment of ND 10-associated proteins and what the benefits are to the cell in combating the induced stress, we plan to identify and characterize the protein composition of ND 10, determine which proteins regulate ND 10 dispersion and analyze the regulatory mechanisms underlying the segregation and dispersion of specific proteins. We will establish the functions of ND10 and their associated proteins by testing for the effects of loss and regulated change of specific ND10-associated proteins on the cells transcriptional profile using knock-out cells and regulatable revertants. We will define the mechanisms used by global effectors such as thermal stress, cadmium and arsenic exposure that activate the regulatory pathways controlled at ND 10. Specifically, we will define the biological significance of the regulated sequestration or release of ND 10-associated proteins in the defense of the cell from toxins and stress.