Histone Lysine Methylation: Structures and Functions

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DESCRIPTION (provided by applicant): Histone lysine methylation is part of the "histone code" that can profoundly influence chromatin function. The overall goal of this project is to understand the substrate and product specificites of histone lysine methyltrasferases (HKMTs) by determining their structures alone and in complex with various substrate histone peptides. Specifically, we propose (1) to investigate the structural basis for substrate specificity (histone tail recognition) and product specificity (mono-, di- or tri-methylation of lysine) of a number of HKMTs; (2) to investigate the biochemical properties of HKMTs and their variants; and (3) to investigate the structural and biochemical properties of several nucleosome-dependent HKMTs. Understanding the structural basis for the product specificity of HKMTs is a central aim of this proposal. Mutations of human HKMTs are frequently associated with diseases including cancer. Because chromatin structure affects gene expression, HMKTs are emerging as major players in the regulation of gene expression and, when deregulated, as inducers of cancer. One of the ultimate goals for the structural and biochemical analysis of HKMTs is to find inhibitors that may be of pharmaceutical value.