Abstract

Transcriptional silencing is an epigenetic mechanism for control of gene expression. Genes located in certain regions of the eukaryotic chromosomes are permanently repressed. This heritable transcriptionally silent state is caused by altered chromatin structure that can be propagated from one generation to the next. Gene silencing has been observed in organisms ranging from yeast to human. Examples of silencing include mating-type loci in fission and budding yeasts, position effect variegation in Drosophila, and X-chromosome inactivation in mammals. In Saccharomyces cerevisiae, several protein complexes are known to be critical for establishing and maintaining transcriptional silencing at several genomic loci. They include the Silent Information Regulator proteins, Sir1p, Sir2p, Sir3p and Sir4p, and several sequence-specific DNA binding proteins, the Origin Recognition Complex (ORC), Rap1p and Abf1p. The structural basis of transcriptional silencing is still poorly understood. We will study the structure and function of the SIR proteins and ORC using X-ray crystallography as our principal method. The result of this study may facilitate an understanding of epigenetic inheritance, DNA repair and aging.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063716-03
Application #
6615632
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Lewis, Catherine D
Project Start
2001-08-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
3
Fiscal Year
2003
Total Cost
$252,320
Indirect Cost

  Institution

Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724

  Publications

Liu, Haiping; Wang, Ju-Yu S; Huang, Ying et al. (2010) Structural basis for methylarginine-dependent recognition of Aubergine by Tudor. Genes Dev 24:1876-81
Li, Yan; Trojer, Patrick; Xu, Chong-Feng et al. (2009) The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate. J Biol Chem 284:34283-95
Connelly, Jessica J; Yuan, Peihua; Hsu, Hao-Chi et al. (2006) Structure and function of the Saccharomyces cerevisiae Sir3 BAH domain. Mol Cell Biol 26:3256-65
Huang, Ying; Myers, Michael P; Xu, Rui-Ming (2006) Crystal structure of the HP1-EMSY complex reveals an unusual mode of HP1 binding. Structure 14:703-12
Hsu, Hao-Chi; Stillman, Bruce; Xu, Rui-Ming (2005) Structural basis for origin recognition complex 1 protein-silence information regulator 1 protein interaction in epigenetic silencing. Proc Natl Acad Sci U S A 102:8519-24
Min, Jinrong; Feng, Qin; Li, Zhizhong et al. (2003) Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell 112:711-23
Landry, Joseph; Sutton, Ann; Hesman, Tina et al. (2003) Set2-catalyzed methylation of histone H3 represses basal expression of GAL4 in Saccharomyces cerevisiae. Mol Cell Biol 23:5972-8
Min, Jinrong; Zhang, Yi; Xu, Rui-Ming (2003) Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev 17:1823-8
Zhang, Zhiguo; Hayashi, Mariko K; Merkel, Olaf et al. (2002) Structure and function of the BAH-containing domain of Orc1p in epigenetic silencing. EMBO J 21:4600-11