Srividya Bhaskara, Ph.D.
Adjunct Assistant Professor, Oncological Sciences
Assistant Professor, Radiation Oncology
Huntsman Cancer Institute
2000 Circle of Hope
Salt Lake City, UT 84112-5550
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) target histones and other non-histone proteins with important roles in cell survival and cell cycle progression. Changing the equilibrium between acetylation and deacetylation can adversely affect the normal functioning of cellular processes and cell cycle progression, and result in the development of various kinds of leukemia and solid tumors. Several HDAC inhibitors are in clinical trials and two of these are FDA approved for the treatment of T-cell lymphoma. One goal of genetic studies of HDACs is to elucidate the function of individual enzymes and to define the actual therapeutic target(s) of HDAC inhibitors, which in turn might pave the way for the design of more specific inhibitors.
Mammalian HDACs are divided into four major classes (I-IV) based on their homology to yeast HDACs. Among Class I HDACs, Hdacs 1, 2 and 3 are of particular interest, as they constitute the catalytic core of several protein complexes involved in multiple nuclear processes, namely, chromatin remodeling, transcription, replication, recombination and repair. Conditional deletion of Hdac3 in in vitro and in vivo models showed that Hdac3 is important for cell cycle progression, double strand break repair and for the maintenance of global chromatin structure. Studies from conditional knockout models further showed that short-term loss of Hdac3 is beneficial, as it causes apoptosis in actively cycling cells. This finding provides the mechanistic explanation for how HDAC inhibitors kill rapidly dividing cancer cells, but not normal cells. On the other hand, long-term loss of Hdac3 in livers led to hepatocellular carcinoma, a finding that highlights the rate-limiting toxicity of HDAC inhibitor therapy.
Hdacs 1 and 2 (the core enzymes in Sin3, NURD and CoREST complexes) interact with myriad proteins both in normal and transformed cells, and they regulate cell cycle progression, proliferation and differentiation. Hdacs 1 and 2, in addition to Hdac3, are important for the maintenance of genome stability. Therefore, the primary focus of our research is to elucidate the functions of Hdacs 1 and 2 in DNA repair and replication, as abnormalities in these two processes can cause genome instability. We use classical and modern biochemical approaches, including cutting-edge molecular biology technologies and mouse gene knockout models, to address important questions related to the link between histone deacetylases and genome maintenance, with potential contributions to translational research.
- Bhaskara, S., Chyla, B.J., Amann, J.M., Knutson, S.K., Cortez, D.K., Sun, Z. -W. and Hiebert, S.W. (2008) Deletion of Histone deacetylase 3 reveals critical roles in S-phase progression and DNA damage control. Molecular Cell, 30: 61-72.
- Bhaskara, S., Knutson, S.K., Jiang G., Chandrasekharan, M.B., Wilson, A.J., Zheng, S., Yenamandra, A., Locke, K., Jia-ling, Y., Summers, A.R., Washington, K., Zhou, Z., Sun, Z. -W., Xia, F., Khabele, D. and Hiebert, S.W. (2010) Histone deacetylase3 is essential for maintenance of chromatin structure and genome stability. Cancer Cell, 18: 436-447.
- Bhaskara, S. and Hiebert, S.W. (2011) Role for histone deacetylase 3 in genome stability maintenance. Cell Cycle, 10(5): 727-728.
Histone deacetylase, genome stability, chromatin, replication, DNA repair, mouse models, cancer, therapeutics.