Defining the function for yeast SMYD lysine methyltransferase

Protein lysine methylation has emerged as a critical regulator of signaling pathways that promote proper growth, development and differentiation in response to environmental signals. The budding yeast enzymes Set5 and Set6 carry the same domain structure as the mammalian SMYD enzymes, which have been identified as regulators of skeletal and cardiac muscle development and linked to cardiac disease. We previously characterized Set5 as a histone H4K5, K8 and K12 methyltransferase that promotes genome stability and gene repression near telomeres and transposable elements in coordination with the H3K4 methyltransferase Set1. Recently we performed mutational analysis of Set5, combined with phosphoproteomics, to identify regulatory mechanisms for its enzymatic activity and subcellular localization. We determined that the interaction of Set5 with chromatin may be associated with DNA-binding activity of its MYND domain, and identified phosphorylation within the C-terminal region as a potential regulator of its catalytic activity. We also determined the role of different domains of Set5 to its regulation of gene expression at subtelomeres. In addition to Set5, the other conserved SMYD protein in yeast is Set6, which has no described biological or biochemical function. Our proteomic data suggest that both Set5 and Set6 methylate multiple, diverse substrates, and new genetic evidence indicates that cells rely on Set5 and Set6 for promoting proper responses to stress. These findings are therefore working to establish yeast as a useful model for understanding SMYD lysine methyltransferase function and their roles in development and disease.