The goal of this research project is to define the functions of two lysine deacetylase enzymes from human cells that modify the chemical structure of other proteins. These changes in chemical structure alter cellular functions; therefore, lysine deacetylases impact many biological processes. However, it is not known which lysine deacetylase controls which cellular function and how, because the specific interactions with each protein within cells have not yet been determined. Better knowledge of the workings of lysine deacetylases will enhance our understanding of how important biological processes such as cellular growth and development are regulated. The project will also strengthen the research environment at Xavier University of Louisiana, a Historically Black College or University, by enabling the participation of undergraduate students in hypothesis-driven, high impact research. Participants will receive training relevant for progression into graduate programs and the scientific workforce. Additionally, the research infrastructure and results will be used to support training of undergraduate students in advanced laboratory courses.
Lysine deacetylases (KDACs) have both enzymatic roles (deacetylation of proteins) and non-enzymatic roles (association into complexes that regulate gene expression and protein function). Despite the widespread acetylation of proteins in human cells, few specific substrates or indirect targets of KDACs have been identified. The project will clarify the specific functions of two KDACs and whether those functions involve catalysis in vivo. The target proteins of the two KDACs will be identified; these targets could be directly deacetylated and/or these targets maybe affected via other regulatory functions. Cell lines containing genomically encoded catalytically inactive KDACs will be used to evaluate the acetylation of intracellular substrate proteins, and these will be validated to verify direct deacetylation, evaluate selectivity, and correlate in vitro reaction rates with in vivo data. The project will also determine the intracellular specificity of KDAC inhibitors believed to target a single KDAC. Overall, this project will greatly expand understanding of how KDACs function in vivo and provide insight into the different mechanisms and pathways through which KDACs exert their effects.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.