TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis

Abstract

Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C α (PKCα) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAi(Met)), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAi(Met). In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAi(Met)-overexpressing cells, PKCα overexpression decreased tRNAi(Met) expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAi(Met) expression with decreased expression of PKCα mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKCα tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.

ALKBH1-Mediated tRNA Demethylation Regulates Translation

“…The cellular level of tRNA iMet is known to significantly impact translation initiation and cell proliferation (Macari et al, 2016; Pavon-Eternod et al, 2013). Indeed, a noticeably increased cell proliferation was observed in the ALKBH1 knockdown cells compared to control cells (Figure 3B).…”

Gene signatures and prognostic values of m1A-related regulatory genes in hepatocellular carcinoma

“…TRMT6 and TRMT61A form a methyltransferase complex and catalyze the methylation of the N1 position on adenosine residues in mRNA. Prior studies have shown that deletion of the TRMT6/61 complex can reduce glioma cell proliferation and increase cell death 33 . Additional studies showed that TRMT6 frameshift mutations could potentially contribute to colorectal cancer 34 .…”

The Emerging Roles of RNA Modifications in Glioblastoma

“…Recently, some RMPs of m 1 A, both writers and erasers, seem to involve in the progression of GBM (Figure 2, m 1 A part). TRMT6 and TRMT61A expression is significantly upregulated in highly aggressive GBM compared with grade II/III gliomas [79]. TRMT61A is a target of HIF1A and is dowregulated after c-Myc inhibition in GBM under hypoxia [138].…”