Abstract

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. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068680-02
Application #
7071250
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Flicker, Paula F
Project Start
2005-06-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$267,756
Indirect Cost

  Institution

Name
Emory University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

Upadhyay, Anup K; Rotili, Dante; Han, Ji Woong et al. (2012) An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 Jumonji demethylases. J Mol Biol 416:319-27
Zhao, Jing; Du, Yuhong; Horton, John R et al. (2011) Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor. Proc Natl Acad Sci U S A 108:16212-6
Upadhyay, Anup K; Cheng, Xiaodong (2011) Dynamics of histone lysine methylation: structures of methyl writers and erasers. Prog Drug Res 67:107-24
Chang, Yanqi; Levy, Dan; Horton, John R et al. (2011) Structural basis of SETD6-mediated regulation of the NF-kB network via methyl-lysine signaling. Nucleic Acids Res 39:6380-9
Upadhyay, Anup K; Horton, John R; Zhang, Xing et al. (2011) Coordinated methyl-lysine erasure: structural and functional linkage of a Jumonji demethylase domain and a reader domain. Curr Opin Struct Biol 21:750-60
Chang, Yanqi; Horton, John R; Bedford, Mark T et al. (2011) Structural insights for MPP8 chromodomain interaction with histone H3 lysine 9: potential effect of phosphorylation on methyl-lysine binding. J Mol Biol 408:807-14
Chang, Yanqi; Sun, Lidong; Kokura, Kenji et al. (2011) MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a. Nat Commun 2:533
Horton, John R; Upadhyay, Anup K; Hashimoto, Hideharu et al. (2011) Structural basis for human PHF2 Jumonji domain interaction with metal ions. J Mol Biol 406:1-8
Levy, Dan; Kuo, Alex J; Chang, Yanqi et al. (2011) Lysine methylation of the NF-?B subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-?B signaling. Nat Immunol 12:29-36
Estève, Pierre-Olivier; Chang, Yanqi; Samaranayake, Mala et al. (2011) A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability. Nat Struct Mol Biol 18:42-8

Showing the most recent 10 out of 43 publications