A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation

This submission is raw imaging data for our manuscript describing the following: Amplification of chromosomal material derived from 12q13-15 is common in human cancer, and believed to result in overexpression of multiple collaborating oncogenes. To define oncogenes involved, we overexpressed genes recurrently amplified in human liposarcoma using a zebrafish model of the disease. We found several genes whose overexpression collaborated with AKT in sarcomagenesis, including the tRNA methyltransferase METTL1. This was surprising because AKT phosphorylates METTL1 to inactivate its enzymatic activity. Indeed, phosphomimetic S27D or catalytically dead alleles phenocopied the oncogenic activity of wild-type METTL1. We found that METTL1 binds the multi-tRNA synthetase complex, which contains many of the cellular aminoacyl-tRNA synthetases, and promotes tRNA aminoacylation, polysome formation and protein synthesis independent of its methyltransferase activity. METTL1-amplified liposarcomas were hypersensitive to actinomycin D, a clinical inhibitor of ribosome biogenesis. Thus, METTL1 stimulates tRNA aminoacylation and protein synthesis independent of its methyltransferase activity, and this tumor-promoting function confers susceptibility to inhibition of ribosome biogenesis.