Monday, February 6, 2023
2/6/2023
PROJECT SUMMARY Advances in research on protein a-N-terminal (Na) methylation have brought to light the important role of this post-translational modification in the regulation of mitosis, chromatin interactions, and DNA repair. Altered methylation levels result in the aberrant expression of N-terminal methyltransferases (NTMTs); this aberrant expression is often implicated in the development of various diseases. However, the function of N-terminal methylation and its role in disease pathogenesis remains poorly characterized. Until recently, N-terminal methylation was believed to only occur on a conserved X-P-K motif of protein substrates and catalyzed by only two enzymes, NTMT1 and NTMT2. Identification of N-terminal methylation on the eukaryotic elongation factor 1 alpha (eEF1A) GKEK motif, a non-canonical NTMT motif, has challenged this paradigm, bringing to light the possibility for additional existing NTMT substrates. The methyltransferase like 13 (METTL13) enzyme has very recently been identified as the methyltransferase responsible for eEF1A N-terminal methylation. METTL13 is a dual methyltransferase that can methylate both the N-terminus of Lys55 of eEF1A through its separate methyltransferase domains, but the biological roles of these methylations are currently unclear. The implication of both METTL13 and eEF1A in the poor prognosis associated with pancreatic, lung, and bladder cancers motivates us to interrogate the role of this novel methylation event in cellular dysfunction. The downstream effects of dysfunctional METTL13 substrate recognition and catalysis and their relation to cancer development are entirely unknown, which highlights a critical need to identify the structural and mechanistic details of METTL13- mediated Na methylation that govern cancer pathogenesis and progression. My central hypothesis is that METTL13-mediated eEF1A Na methylation may serve a distinct functional role from eEF1A Lys55 methylation and their dysregulation may yield different biological outcomes in a tissue-specific manner. The long-term goals of this proposal are to (1) generate a comprehensive understanding of the substrate recognition, regulation, and function of Na methylation catalyzed by METTL13 and (2) determine the relation between METTL13-mediated Na methylation and cancer progression. The results from this research will clarify the biological role of Na methylation and define structural features of METTL13 that have the potential to inform future targeted cancer therapies.
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