Lysine residues on the N-terminal tails of histones in chromatin are targets for histone acetyltransferases (HATs) and histone deacetylases (HDACs) in eukaryotes. Regulation of reversible acetylation on histones and other proteins by these two classes of enzymes plays significant roles in controlling various processes in the cell including DNA compaction and replication, transcription, cell structure, and intracellular signaling. All eukaryotic organisms have several different HDACs divided into distinct classes, yet the biological roles of each individual enzyme are still not clear. To understand the biological properties of individual HDACs, we first characterized six different Drosophila HDACs. We determined that each HDAC is expressed at distinct stages of development independent of classification. We found that overexpression of each HDAC regulates a unique transcriptional profile of target genes in distinct categories. Finally, we showed differential sensitivity of each enzyme to various HDAC inhibitors. These results indicated that each individual HDAC plays different roles in regulating genes involved in various biological processes.
One of the most studied biological process regulated by HDACs is lifespan that can be extended with increased expression of the HDAC sir2 in diverse organisms including yeast, C. elegans, and Drosophila melanogaster. However, other studies in yeast have shown that Sir2 itself may prevent life extension, and high expression levels of Sir2 can be toxic to yeast and mouse cells. This conflicting evidence highlights the importance of understanding the mechanisms by which Sir2 expression or activation affects survival of organisms in vivo. In order to investigate the downstream signaling pathways affected by Sir2 in Drosophila, we generated transgenic flies expressing sir2. Overexpression of sir2 in Drosophila promotes caspase-dependent, but p53-independent apoptosis that is mediated by the JNK and FOXO signaling pathways. Furthermore, we found that a loss-of-function sir2 mutant partially prevents apoptosis induced by UV-irradiation in the eye, suggesting an endogenous role of sir2 in mediating the apoptotic response. Together, these results suggest a novel role for Sir2 in the regulation of cell survival and death in Drosophila.
|Advisor:||Min, Kyung-Tai, Johnson, Diana|
|Commitee:||Ceryak, Susan, Chiaramello, Anne E., Fischbeck, Kenneth, Hu, Valerie|
|School:||The George Washington University|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 69/07, Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics|
|Keywords:||Apoptosis, Cell death, Cell survival, Deacetylase, Drosophila, Histone deacetylases, Sir2|
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