Cell 176, 491–504 (2019)

Nat. Commun. 9, 3411 (2018)

Eukaryotic elongation factor 1A (eEF1A) is a GTPase that regulates protein synthesis as a component of the translational machinery and has been observed to undergo dimethylation at K55 (eEF1AK55me2). However, the functional relevance of this modification and the enzymes that mediate it were not known. Liu et al. screened a CRISPR–Cas9 knockout collection of lysine methyltransferases, whereas Jakobsson et al. utilized a MS-based quantitative interaction peptide pull-down screen to identify METTL13 as a methyltransferase for eIF1A. Liu et al. detected high levels of eEF1AK55me2 in pancreatic and lung cancer tissues, and knockdown of METTL13 or eIF1A2 blocked cancer cell proliferation. In vitro GTPase assays demonstrated increased catalytic activity of methylated eIF1A, while METTL13 knockdown decreased protein synthesis in cancer cells, suggesting that METTL13-mediated methylation of eEF1A may promote oncogenesis through increased protein synthesis. Finally, Liu et al. performed a cell-based screen to identify compounds that were effective against METTL13-deficient pancreatic cancer cells and revealed a synthetic lethality with PI3K-mTOR and MAPK pathway inhibitors, demonstrating that METTL13 may be a targetable node for cancer therapy.