Function and Regulation of Lysine Methylation Dependent Proteolysis - Project Summary Emerging evidence indicates that many non-histone proteins can be lysine methylated and our studies have shown that addition of a methyl group to a specific lysine residue in non-histone proteins leads to the rapid proteolysis of the modified proteins by ubiquitin dependent proteolysis. We propose to investigate the mechanism by which the methylated proteins are proteolyzed by ubiquitin dependent proteolysis. Two classes of methyltransferases, SETD7 and KMT2/MLL family members, can methylate non-histone proteins and the methylated lysine residues in target proteins serve as the signals for proteolysis. We have identified multiple methyl lysine reader proteins and two independent ubiquitin ligase complexes for the proteolysis of methylated protein substrates. The substrate proteins regulate a wide variety of important biological processes including the control of various stem cells/progenitor cells including embryonic stem cells, neural stem cells, and hematopoietic stem cells, epigenetic regulation of histone and DNA methylation, and ATP dependent chromatin remodeling during embryonic and adult development. Alterations of these important biological processes lead to cancers and other disorders. Since lysine methylation dependent proteolysis is a new research area, we propose to systematically investigate the mechanism by which target proteins are modified and proteolyzed by lysine methylation to establish a new paradigm that controls the self-renewal and differentiation of different types of stem cells, development, cancers and other disorders. Our specific aims are: 1) To investigate the dynamic methylation/demethylation mechanism for proteolysis; 2) To examine how specific ubiquitin ligase complexes cooperate the methyl reader proteins to interact with the methylated substrates for proteolysis; 3) To develop animal models to investigate the significance of methylation dependent proteolysis. Elucidation of the proposed research will help understand how the dose dependent protein regulation and cell fate determination are regulated in various stem/progenitor and related cells during development and will help to understand pathological alterations in the methylation dependent proteolysis pathways that should shed new lights for the development of novel therapeutic strategies for various human diseases such as cancers and other developmental disorders.
