The post-translational modification of proteins is central to genome regulation and cell signaling. Lysine acetyl transferase (KATs) were formerly known as histone acetylases (HATs) as they acetylated histones and thereby control transcription. However, recent studies strongly suggest that the acetylation mark is far more common protein modification with possibly over 7,000 acetylated proteins in the human proteome. There are numerous KATs and currently available small molecule based inhibition methods are not uniquely specific while RNAi based gene knock down studies can fail to provide details related to the true role of any enzyme as compensatory acetylation may occur. To address this problem, we have developed a method to selectively turn-on the activity of individual enzymes utilizing small molecules. We have successfully created the first generation of ligand inducible split-KATs, GCN5 and PCAF. Here inactive N- and C fragments are attached to the FKBP/FRB proteins, and heterodimerization is achieved by the small molecule ligand, rapamycin. We are currently using this approach for designing several new KATs, Myst2 and HAT1, which belong to different families, with the intention of exploring the possibility to establish temporal and spatial control over multiple KATs simultaneously in relevant cell lines.<br/> <br/> <br/>

Spatial and temporal control of lysine acetyl transferases (KATs): Ligand gated split KATs

253rd National Meeting (2017)

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