Mechanisms & Inhibition of Histone Acetyltransferases

该申请是GM64327的竞争性续期申请，涉及两个组蛋白乙酰转移酶（HAT）家族p300/CBP和PCAF/GCN5的催化机制、调控和合成抑制剂。hat被认为通过催化组蛋白上关键赖氨酸残基的乙酰化，通过染色质重塑来调节基因表达。它们也被认为是多种转录因子和其他蛋白质乙酰化的催化剂。虽然在过去的8年里，人们对hat的分子克隆已经有了很多了解，但对hat的催化机制、调控和功能的了解仍然存在很大的差距，包括生物医学上重要的p300/CBP和PCAF/GCN5家族。

DESCRIPTION (provided by applicant) This proposal is a competing renewal application of GM64327 that concerns the catalytic mechanisms, regulation, and synthetic inhibitors of two histone acetyltransferase (HAT) families p300/CBP and PCAF/GCN5. HATs are proposed to regulate gene expression via chromatin remodelling by catalyzing acetylation of key lysine residues on histones. They are also thought to serve as catalysts for the acetylation of a variety of transcription factors and other proteins. Although much has been learned in the past 8 years about HATs since their molecular cloning, there are still large gaps in our understanding about the catalytic mechanisms, regulation, and functions of HATs including the biomedically important p300/CBP and PCAF/GCN5 families. Potent and selective cell permeable HAT inhibitors have yet to be reported for these enzymes. The specific aims of this proposal are: i) define the mechanistic role of the recently discovered 'activation loop' on the catalytic action of p300 HAT, ii) clarify the effects of the p300 activation loop and autoacetylation in mediating protein-protein interactions, iii) define the role of a structurally flexible loop in the catalytic mechanism and substrate selectivity of PCAF/GCN5, and iv) develop potent and selective cell permeable HAT inhibitors and apply them to address biological questions of HAT function. The studies on mechanism and regulation of HATs should lead to a broadening of our understanding of normal and pathophysiologic processes related to gene expression. Selective inhibitors of HAT enzymes may be useful in the treatment of cancer, HIV, and other diseases related to the dysregulation of protein acetylation.