STRUCTURAL STUDY OF EPIGENETIC MODIFICATIONS

Cornell University, Ithaca NY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Epigenetic modifications, including DNA methylation, histone covalent modifications and ATP-dependent remodeling of nucleosomes, interact to play a fundamental role in the regulation of gene expression and DNA replication, recombination and repair, and they are responsible for stem cell development and differentiation. Importantly, these modifications impact the aging process and a number of cellular pathologies, such as cancers and degenerative diseases. Histone modifications serve as the binding platform for effector proteins or complexes that alter the structure of chromatin and modulate gene activity. The histone code hypothesis posits that specific modifications or combinations thereof dictate specific outcomes associated with a particular chromatin structure (heterochromatic vs euchromatic) and gene activation state. The model predicts that these modifications create targets that can be recognized by effector molecules. As such, enzymes that catalyze the modifications have been termed writers, those that recognize the marks, readers;and finally, erasers are enzymes that remove such marks from histones. Importantly, such enzymes and binding modules are novel targets for therapeutics. The overriding aim of this project is therefore to generate a sspectrum of structures for enzymes modifying DNA and histone H3 lysines 4, 9, 27, and 36, respectively.