H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.
Histone deacetylases (HDACs) are enzymes that regulate the functions of histone proteins by catalyzing the removal of acetyl groups from lysine residues. They play a pivotal role in the regulation of gene transcription and are indispensable in numerous eukaryotic biological processes involving chromatin. Results from many studies suggest that HDACs control cell cycle progression, cell proliferation, and differentiation. Remarkably, recent studies reveal that many "histone" deacetylases possess the ability to deacetylate not only histones but also non-histone protein substrates. Ataxia telangiectasia (AT) is a rare, autosomal recessive, progressive, neurodegenerative childhood disease that affects the brain and multiple other body systems. About 20% of AT patients develop cancer, most frequently acute lymphocytic leukemia or lymphoma. The ataxiatelangiectasia group D complementing (ATDC) gene was originally isolated on the basis of its ability to complement the ionizing radiation sensitivity defect of AT group D fibroblasts. Later analysis revealed that ATDC does not affect radioresistant DNA synthesis and is most likely not mutated in any AT patients. Therefore, although the ATDC gene product acts indirectly to suppress radiosensitivity in AT cells, the mechanism by which ATDC complements radiosensitivity in AT cells and how ATDC activities and functions are regulated are entirely unknown. Preliminary results indicate that ATDC is an acetylated protein, and its acetylation status is closely controlled by HDAC9. This revised proposal, in response to the ARRA, will test the overall hypothesis that HDAC9 is critically involved in regulating the activities and functions of a non-histone protein, ATDC. The long-term goal of this project is to explore novel biological roles of HDAC9 and to obtain a complete understanding of how HDAC9 regulates important cellular processes by targeting non-histone proteins. Immediate emphasis will be placed on clarifying the potential involvement of HDAC9 in the deacetylation of the ATDC protein that consequently influences a pathway that could affect radiosensitivity in AT cells. Understanding the function and regulation of ATDC, and its mechanism of suppression of radiosensitivity in AT cells, will provide important insights into alternative pathways involved in the cellular response to ionizing radiation. Additionally, abnormal HDACs are strongly correlated with many human maladies, such as cancer. Therefore, a thorough understanding of the role of HDAC9 in the modification of ATDC will provide not only tremendous insight into the novel functions and mechanisms of action of HDACs but also potential diagnostic and therapeutic approaches for the treatment of diseases. Description of changes: The objectives and hypotheses of this revised proposal remain unchanged. As a result, there are minimal changes in this revised abstract section.