In recent years, a variety of new posttranslational protein modifications occurring on histone proteins have been discovered. This includes lysine crotonylation, an enzymatically regulated epigenetic histone mark. Here we report the discovery of a new type of posttranslational modification occurring on histones, lysine methacrylation. Methacryllysine is a structural isomer of crotonyllysine. We validated the identity of the modification using mass spectrometry for co-elution, ozonolysis, and isotopic labeling experiments. We generated and validated pan specific and site specific antibodies for this mark. We report that HAT1 can enzymatically catalyze the addition of this modification, representing the first published report of HAT1 using a substrate other than acetyl-CoA. Here we also provide the first report that SIRT1 and SIRT2 catalyze the removal of this modification.



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