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Studies on the molecular basis of substrate specificity and inhibition of the GCN5/PCAF histone acetyltransferases.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Studies on the molecular basis of substrate specificity and inhibition of the GCN5/PCAF histone acetyltransferases.
Author:	Poux, Arienne Nicole.
Description:	155 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4922.
Notes:	Supervisor: Ronen Marmorstein.
Contained By:	Dissertation Abstracts International64-10B.
Subject:	Chemistry, Biochemistry.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3109212
ISBN:	0496567551

Studies on the molecular basis of substrate specificity and inhibition of the GCN5/PCAF histone acetyltransferases.
Poux, Arienne Nicole.

Studies on the molecular basis of substrate specificity and inhibition of the GCN5/PCAF histone acetyltransferases. [electronic resource] - 155 p.

Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4922.

Thesis (Ph.D.)--University of Pennsylvania, 2003.

Histone acetyltransferase (HAT) enzymes play a critical role in the control of gene expression by acetylating specific lysine residues within nucleosomal N-terminal histone tails. Histone acetylation is believed to be one step in a cascade that modulates transcriptional signaling, where distinct patterns of covalent modifications act synergistically to affect changes in transcriptional activity. An essential component of covalent modification by HAT proteins lies in their ability to distinguish specific lysine-bearing substrates. Indeed, the GCN5/PCAF family of HAT enzymes acetylate specific lysine residues within a diverse array of substrates, including histones, modified histones, and non-histone proteins. In the first two parts of this thesis, the substrate specificity of the GCN5/PCAF HAT family of enzymes is probed. First, the crystal structure of Tetrahymena GCN5 (tGcn5) bound to Coenzyme A and either a phosphorylated or non-phosphorylated histone H3-derived peptide was determined to reveal the mechanism underlying the synergic relationship between histone H3 phosphorylation and acetylation. In the second study, the ability of GCN5/PCAF HATS to recognize specific lysine residues within hi stone H4 and the tumor suppressor p53 was also investigated at the structural level. Together with associated biochemical experiments, these studies address the overall question of GCN5/PCAF HAT substrate specificity at a molecular level. Aberrant activity in HAT function has been correlated with cancer and other disease. In the final study, this relationship is addressed through the crystal structure of a bisubstrate inhibitor bound to tGcn5, as well as related biochemical studies with this inhibitor. These studies provide important information regarding the enzyme catalytic cycle as well as a scaffold for the development of more potent HAT inhibitors.

ISBN: 0496567551Subjects--Topical Terms:

226900
Chemistry, Biochemistry.

Studies on the molecular basis of substrate specificity and inhibition of the GCN5/PCAF histone acetyltransferases.
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520 # $a Histone acetyltransferase (HAT) enzymes play a critical role in the control of gene expression by acetylating specific lysine residues within nucleosomal N-terminal histone tails. Histone acetylation is believed to be one step in a cascade that modulates transcriptional signaling, where distinct patterns of covalent modifications act synergistically to affect changes in transcriptional activity. An essential component of covalent modification by HAT proteins lies in their ability to distinguish specific lysine-bearing substrates. Indeed, the GCN5/PCAF family of HAT enzymes acetylate specific lysine residues within a diverse array of substrates, including histones, modified histones, and non-histone proteins. In the first two parts of this thesis, the substrate specificity of the GCN5/PCAF HAT family of enzymes is probed. First, the crystal structure of Tetrahymena GCN5 (tGcn5) bound to Coenzyme A and either a phosphorylated or non-phosphorylated histone H3-derived peptide was determined to reveal the mechanism underlying the synergic relationship between histone H3 phosphorylation and acetylation. In the second study, the ability of GCN5/PCAF HATS to recognize specific lysine residues within hi stone H4 and the tumor suppressor p53 was also investigated at the structural level. Together with associated biochemical experiments, these studies address the overall question of GCN5/PCAF HAT substrate specificity at a molecular level. Aberrant activity in HAT function has been correlated with cancer and other disease. In the final study, this relationship is addressed through the crystal structure of a bisubstrate inhibitor bound to tGcn5, as well as related biochemical studies with this inhibitor. These studies provide important information regarding the enzyme catalytic cycle as well as a scaffold for the development of more potent HAT inhibitors.
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