Histone proteins and the nucleosomal complexes they form are the fundamental units of eukaryotic chromatin. How nucleosomal filaments are folded into higher-order structures or how distinct functional domains are established and maintained remains poorly understood. One long-range objective of this proposal is to understand the molecular mechanisms of chromatin- mediated gene activation. Another important issue being addressed is how the chromatin fiber is condensed to allow for the faithful segregation of chromosomes, an essential step in cell cycle progression. The overall goal of this research program is to investigate the nature and biological significance of core histone phosphorylation as it relates to both of the above cellular processes. To achieve this goal, we will employ genetics, biochemical and immunocytochemical in a variety of model systems. The highly conserved nature of histone proteins, as well as the phosphorylation events and the relevant enzyme systems involved, underscore the fundamental nature of the chromatin problem with respect to gene regulation and chromosomal dynamics. Just as studies on histone acetylation have led to a wealth of new insights into mechanisms of transcription, we anticipate that insights into histone phosphorylation will pave the way for a better understanding of transcriptional regulation as well as chromosome transmission. Understanding the physiological targets and sites phosphorylated by these enzymes is of paramount importance. The close association of histone kinases, such as aurora kinase, with oncogenesis provides strong support for an emerging view that covalent modification of histones, including phosphorylation at defined sites, play a vital role in the regulation of chromatin and chromosome dynamics with far-reaching implications for human biology and disease.
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