Chromatin is the nucleoprotein structure that enables chromosomal DNA to be condensed and packaged in eukaryotic nuclei. The primary protein components of chromatin are the core histones (H2A, H2B, H3, and H4). Chromatin structure plays an active role in the regulation of many cellular processes that involve accessing chromosomal DNA, such as transcription, DNA replication, recombination and DNA repair. As the regulation of many aspects of normal cell growth requires the tight control of these processes, it is important to understand how they are influenced by, and interact with, chromatin structure. Much of the regulatory potential of the core histones resides small, positively charged domains called the NH2-terminal tails. The core histone NH2-terminal tails are subject to a wide range of post-translational modifications, of which acetylation is the most extensively characterized. The acetylation of histones, which appears to be a fundamental mechanism by which cells regulate chromatin structure, occurs on lysine residues, negating their positive charge. The acetylation state of the histones is governed by the interplay of enzymes that add acetyl groups (histone acetyltransf erases) and enzymes that remove them (histone deacetylases). Histone acetyltransferases can be divided into two classes based on substrate specificity and cellular localization. Type A histone acetyltransferases are nuclear enzymes that acetylate histones in a chromatin context. Type B histone acetyltransferases acetylate free histones and can be found in the cytoplasm. While type A histone acetyltransferases, such asGcn5p, have been conclusively linked to the regulation of gene expression, little is known about the function of type B histone acetyltransferases. However, using the yeast type B histone acetyltransferase Hat1 p as a model, we have recently obtained evidence that these enzymes are involved in silent chromatin structure and DNA damage repair. The primary goal of our research is to extend these results, using a combination of molecular genetics and biochemistry, to define the in vivo role of type B histone acetyltransferases. This goal will be pursued through three specific aims. The first is to determine the mechanism(s) through which Hat1p affects the silent chromatin structure found near yeast telomeres. The second is to characterize the involvement of Hat1p and chromatin structure the repair of DNA double strand breaks. Third, we will isolate and characterize novel type B histone acetyltransferases.
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