Methyltransferase-independent effects of METTL1 on RNA expression and translation efficiency

The overall study is focused on investigating oncogenic transformation by a methyltransferase-independent function of METTL1. METTL1, which is best-known for its ability to methylate tRNAs, is recurrently amplified in human liposarcoma, a disease characterized by aberrant AKT activation. We found that METTL1 overexpression accelerates the onset of AKT-induced liposarcoma in a zebrafish model of the disease. This was surprising because AKT was previously shown to phosphorylate METTL1 and inactivate its methyltransferase 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.This SRA submission is the raw data for ribosome profiling (Ribo-seq) and RNA sequencing (RNA-seq) analysis of mouse embryonic fibroblasts (MEFs) transduced with pairs of transgenes: EGFP + dTomato (negative controls), EGFP + a constitutively active AKT2 allele (hereafter, AKT), a catalytically dead METTL1 allele (hereafter, METTL1-CD) + dTomato, and METTL1-CD + AKT. Analysis of these data revealed that METTL1-CD has modest effects on mRNA expression or relative translation efficiency. While we cannot rule out the possibility that METTL1 has some transcript-selective effects below the limit of detection of these assays, these are not prominent effects. These data thus support a model in which the methyltransferase-independent oncogenic function of METTL1 is mediated by global stimulation of tRNA aminoacylation, protein synthesis and tumor cell growth.