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.