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METTL6 is a tRNA m3C methyltransferase that regulates translation and cell proliferation

ABSTRACT: Here, we identified METTL6 as a bona fide tRNA methyltransferase, catalysing the formation of 3-methylcytidine (m3C) at C32 of specific serine tRNA isoacceptors. Accordingly, deletion of METTL6 in mouse stem cells results in changes in ribosome occupancy and RNA levels, as well as a spontaneous loss of pluripotency

ORGANISM(S): Mus musculus

PROVIDER: GSE144866 | GEO | 2020/06/18

REPOSITORIES: GEO

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m3C HAC-Seq analysis in HEK293T WT cells, METTL2A/2B knockout cells, METTL6 knockout cells, METTL2A/2B/6 knockout cells.

Project description:The ‘epitranscriptome’ includes a diversity of RNA modifications that influence gene expression. N3-methylcytidine (m3C) mainly occurs in the anticodon loop (position C32) of certain tRNAs yet its role is poorly understood. Here, using HAC-Seq, we report comprehensive METTL2A/B-, METTL6-, and METTL2A/B/6-dependent m3C profiles in human cells. METTL2A/B modifies most tRNA-Arginine and tRNA-Threonine members, whereas METTL6 modifies the tRNA-Serine family. However, decreased m3C32 on tRNA-Ser-GCT isodecoders was only observed with combined METTL2A/B/6 deletion. Ribo-Seq revealed altered translation of genes related to cell cycle and DNA repair pathways in METTL2A/2B/6-deficient cells, and these mRNAs are enriched in AGU codons that require tRNA-Ser-GCT for translation. These results, supported by reporter assays, help explain the observed slowed proliferation, altered cell cycle, and increased Cisplatin-sensitivity phenotypes of METTL2A/B/6-deficient cells. Thus, we define METTL2A/B/6-dependent methylomes and uncover a particular requirement of m3C tRNA modification for Serine codon-biased mRNA translation of cell cycle, and DNA repair genes.

2024-07-17 | GSE223469 | GEO

Ribosome Footprinting (RiboSeq) analysis of mRNA translation in HEK293T WT and METTL2A/2B/6 knockout cells

2024-07-17 | GSE223418 | GEO

Nucleotide resolution profiling of m3C RNA modification by HAC-seq

Project description:We report a m3C-specific high-throughput sequencing techinque, Hydrazine-Aniline Cleavage sequencing (HAC-seq) to profile the m3C methylome at single-nucleotide resolution. We apply HAC-seq to analyze ribosomal RNA-depleted total RNA from MCF7 cells. We find that tRNA are the predominant m3C-modified RNA species. We find no evidence of m3C-modification of mRNA or other non-coding RNAs at comparable levels to tRNA in MCF7 cells.

2020-11-20 | GSE157682 | GEO

Epitranscriptomic regulation of cortical neural stem cell maintenance via Mettl8-dependent mitochondrial tRNA m3C modification

Project description:Increasing evidence implicates critical roles of various epitranscriptomic RNA modifications in different biological processes. Methyltransferase METTL8 installs 3-methylcytosine modification of mitochondrial tRNAs in vitro, however, its role in intact biological systems is completely unknown. Here we show that Mettl8 is localized in the mitochondria and installs m3C in mitochondrial tRNASer(UCN)/Thr in mouse embryonic cortical neural stem cells. At molecular and cellular levels, Mettl8 deletion in cortical neural stem cells leads to reduced mitochondrial protein translation and attenuated respiration activity. At the functional level, conditional Mettl8 deletion in mice results in impaired embryonic cortical neural stem cell maintenance in vivo, which can be rescued by pharmacologically enhancing mitochondrial functions. Similarly, METTL8 regulates mitochondrial protein expression and neural stem cell maintenance in human forebrain cortical organoids. Together, our study reveals a conserved epitranscriptomic mechanism of Mettl8 and mitochondrial tRNA m3C modification in maintaining embryonic cortical neural stem cells in mice and humans.

2023-01-12 | GSE214445 | GEO

Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs

Project description:Mitochondria contain a specific translation machinery for the synthesis of respiratory chain components encoded on the mitochondrial genome. Mitochondrial tRNAs (mt-tRNAs) are also generated from the mitochondrial genome and, similar to their cytoplasmic counterparts, are modified at various positions. Here, we find that the RNA methyltransferase METTL8, is a mitochondrial protein that facilitates m3C methylation at position C32 of mt-tRNASer(UCN) and mt-tRNAThr. METTL8 knock out cells show reduced and over expressing cells enhanced respiratory chain activity. In pancreatic cancer, METTL8 levels are high, which correlates with patient survival. Indeed, METTL8 up regulation stimulates respiratory chain activity in these cells. Ribosome occupancy analysis using ribosome profiling revealed ribosome stalling on mt-tRNASer(UCN) and mt-tRNAThr codons and mass spectrometry analysis of native ribosomal subcomplexes unraveled reduced respiratory chain incorporation of the mitochondria encoded proteins ND6 and ND1. A well-balanced translation of mt-tRNASer(UCN) and mt-tRNAThr codons through METTL8-mediated C32 methylation might therefore provide optimal respiratory chain compositions and function.

2023-01-02 | GSE180400 | GEO

METTL6 is a tRNA m3C methyltransferase that regulates translation and cell proliferation

Project description:METTL6 is a tRNA m3C methyltransferase that regulates translation and cell proliferation

| PRJNA605175 | ENA

METTL6 is a tRNA m3C methyltransferase that regulates translation and tumor cell proliferation

Project description:METTL6 is a tRNA m3C methyltransferase that regulates translation and tumor cell proliferation

| PRJEB37209 | ENA

METTL8 is required for 3-methylcytosine modification in human mitochondrial tRNAs

Project description:A subset of eukaryotic tRNAs is methylated in the anticodon loop to form the 3-methylcytosine (m3C) modification. In mammals, the number of tRNAs containing m3C has expanded to include mitochondrial (mt) tRNA-Ser-UGA and mt-tRNA-Thr-UGU. Whereas the enzymes catalyzing m3C formation in nuclear-encoded cytoplasmic tRNAs have been identified, the proteins responsible for m3C modification in mt-tRNAs are unknown. Here, we show that m3C formation in human mt-tRNAs is dependent upon the Methyltransferase-Like 8 (METTL8) enzyme. We find that METTL8 is a mitochondria-associated protein that interacts with mitochondrial seryl-tRNA synthetase along with mt-tRNAs containing m3C. Human cells deficient in METTL8 exhibit loss of m3C modification in mt-tRNAs but not nuclear-encoded tRNAs. Consistent with the mitochondrial import of METTL8, the formation of m3C in METTL8-deficient cells can be rescued by re-expression of wildtype METTL8 but not by a METTL8 variant lacking the N-terminal mitochondrial localization signal. Notably, METTL8-deficiency in human cells causes alterations in the native migration pattern of mt-tRNA-Ser-UGA suggesting a role for m3C in tRNA folding. Altogether, these findings demonstrate that METTL8 is required for m3C formation in mitochondrial tRNAs and uncover a potential role for m3C modification in mitochondrial tRNA structure.

2022-05-19 | PXD030418 | Pride

Epitranscriptomic regulation of cortical neural stem cell maintenance via Mettl8-dependent mitochondrial tRNA m3C modification

Project description:Epitranscriptomic regulation of cortical neural stem cell maintenance via Mettl8-dependent mitochondrial tRNA m3C modification

| PRJNA885431 | ENA

The HisRS-like domain of GCN2 is a pseudoenzyme that can bind uncharged tRNA - HX-MS Data

Project description:GCN2 is a stress response kinase that phosphorylates the translation initiation factor eIF2to inhibit general protein synthesis when activated by uncharged tRNA and stalled ribosomes. The presence of a HisRS-like domain in GCN2, normally associated with the ability to bind and aminoacylate tRNAs, led to the hypothesis that eIF2 kinase activity is regulated by the direct binding of this domain to uncharged tRNA. Here we solved the structure of the HisRS-like domain in the context of full-length GCN2 by cryoEM. Structure and function analysis shows the HisRS-like domain of GCN2 has lost tRNA charging, ATP binding, and histidine binding activity but retains the ability to bind tRNA. Hydrogen deuterium exchange mass spectrometry (HX-MS), site-directed mutagenesis and computational docking experiments support a tRNA binding model that overlaps with but is partially shifted from that employed by bona fide HisRS enzymes. These results demonstrate that the HisRS-like domain of GCN2 is a pseudoenzyme and advance our understanding of GCN2 regulation and function.

2024-02-01 | PXD049090 | Pride

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