2.1.1.203: tRNA (cytosine34-C5)-methyltransferase
This is an abbreviated version!
For detailed information about tRNA (cytosine34-C5)-methyltransferase, go to the full flat file.
Word Map on EC 2.1.1.203
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2.1.1.203
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5-methylcytosine
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anticodon
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homocysteine
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wobble
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ualcan
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5-formylcytosine
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biallelic
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omnibus
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shrinkage
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hyperhomocysteinemia
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encephalomyopathy
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nsun2-mediated
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epitranscriptome
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early-onset
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medicine
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pharmacology
- 2.1.1.203
- 5-methylcytosine
-
anticodon
- homocysteine
-
wobble
-
ualcan
- 5-formylcytosine
-
biallelic
-
omnibus
-
shrinkage
-
hyperhomocysteinemia
- encephalomyopathy
-
nsun2-mediated
-
epitranscriptome
-
early-onset
- medicine
- pharmacology
Reaction
Synonyms
5-methylcytosine RNA methyltransferase, cytosine-5 RNA methyltransferase, cytosine-5 tRNA methyltransferase, DnmA, EC 2.1.1.29, hTrm4, M5C RNA methyltransferase, NOP2/Sun domain family member 2, NSUN2, NSUN3, NSUN3 methylase, PMT1, RCMT, RNA:m5C methyltransferase, SAKI, substrate of AIM-1/Aurora kinase B
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General Information on EC 2.1.1.203 - tRNA (cytosine34-C5)-methyltransferase
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GENERAL INFORMATION 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
evolution
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nonessential tRNA modifications by methyltransferases are evolutionarily conserved and have been reported to stabilize mature tRNA molecules and prevent rapid tRNA decay. The tRNA modifying enzymes, NSUN2 and METTL1, EC 2.1.1.33, are mammalian orthologues of yeast Trm4 and Trm8, which are required for protecting tRNA against tRNA decay
malfunction
metabolism
physiological function
additional information
malfunction
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in mice, a Nsun2 knockout, ablation of Nsun2 through the deletion of exon 8, leads to the gross small-size phenotype indicating weight loss with 30% reduction at 3 months old, and partial alopecia at about 10 months old, suggesting a role for NSUN2 in skin homeostasis. Nsun2-/- males are sterile. Heterozygous mice appear normal and have no visible phenotype
malfunction
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mutation G679R causes NSUN2 to fail to localize within the nucleolus. NSUN2, besides other RNA-methyltransferase-encoding genes, is involved in neurological disorders like intellectual disability, also called mental retardation, phenotypes, overview
malfunction
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combined knockdown of NSUN2 and METTL1, EC 2.1.1.33, in HeLa cells drastically potentiate sensitivity of cells to 5-fluorouracil, but does not affect cisplatin- and paclitaxel-induced cytotoxicity, synergistic effects of NSUN2 and METTL1 double knockdown, which causes rapid tRNA(ValAAC) degradation induced by destabilizing 5-fluorouracil
malfunction
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in the absence of NSun2, tRNAs lack specific cytosine-5 methylation modifications, which can cause reduced protein translation rates. In NSun2-depleted testes, genes encoding Ddx4, Miwi, and Tudor domain-containing (Tdr) proteins are repressed, indicating that RNA-processing and posttranscriptional pathways are impaired. Proteins of the RNA-processing machinery are reduced in NSun2-/- testes. Loss of NSun2 specifically blocks meiotic progression of germ cells into the pachytene stage, as spermatogonial and Sertoli cells are unaffected in knockout mice. Lack of NSun2 causes a block of progression of the first prophase of male meiosis at the zygotene-pachytene stage before the chromatoid bodies first appear in the cytoplasm at the late pachytene stage. Phenotype, detailed overview
malfunction
loss-of-function mutations in the human NSUN3 gene causes mitochondrial disorders. NSUN2-depleted cells show attenuated changes to protein synthesis rates. Protein synthesis rates of rescued NSUN2-/- cells (NSUN2) are comparable to NSUN2+/+ cells and slightly, but not significantly, reduced when the enzymatic dead version of NSUN2 K190M is expressed. Cell stress causes a strong but temporary reduction of protein synthesis, which is attenuated by loss of NSUN2. Stress induces a site-specific and dynamic loss of m5C. Mitochondrial activity is reduced and catabolic pathways enhanced in the absence of NSUN2
malfunction
mutation in (cytosine-5) RNA methyltransferase NSun2, which targets mostly tRNAs, impacts the expression of mobile element-derived sequences and affects DNA repeat integrity in Drosophila melanogaster. Reduced tRNA stability in the RCMT mutant indicates that tRNA-dependent processes affect mobile element expression and DNA repeat stability. NSun2 function affects mobile element expression and genome integrity in a heat shock-independent fashion. Reduced tRNA stability in both RCMT mutants indicates that tRNA-dependent processes affect mobile element expression and DNA repeat stability. NSun2 mutants show heat-shock-independent transposable element (TE) expression changes
malfunction
mutation of the cysteine in motif IV in human NSUN3 to alanine or serine results in a stable covalent intermediate
malfunction
mutation of the cysteine in motif IV in human NSUN3 to alanine or serine results in a stable covalent intermediate. Lack of NSUN3 (or ALKBH1) impairs mitochondrial translation, leading to decreased cell proliferation. Mutations in NSUN3 that lead to either aberrant splicing and frameshifting (p.Glu42Valfs*11) or the introduction of a premature stop codon (c.295C>T/p.Arg99*) have been detected in patients with a mitochondrial deficiency disorder characterized by developmental disability microcephaly, failure to thrive, recurrent increased lactate levels in plasma, muscular weakness, proximal accentuated, external ophthalmoplegia, and convergence nystagmus. Furthermore, mitochondrial disease-associated point mutations with the gene encoding mt-tRNAMet that lead to A37G and C39U substitutions have been shown to impede methylation of C34 by NSUN3. In both cases, lack of NSUN3-mediated modification impairs mitochondrial translation, leading to reduced mitochondrial function. Reduced mitochondrial translation affects the normal differentiation program
malfunction
NSUN3-knockout cells show strong reduction in mitochondrial protein synthesis and reduced oxygen consumption, leading to deficient mitochondrial activity. Reconstitution of formation of 5-methylcytidine (m5C) at position 34 (m5C34) on mt-tRNAMet with recombinant NSUN3 in the presence of AdoMet. Two disease-associated point mutations in mt-tRNAMet that impair m5C34 formation by NSUN3, are determined, indicating that a lack of f5C34 has pathological consequences. Loss of NSUN3 causes mitochondrial dysfunction, phenotype, overview
metabolism
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formation of a covalent complex between dual-cysteine RNA:m5C methyltransferases and methylated RNA provides a unique means by which metabolic factors can influence RNA. By controlling the degree of formation of the enzyme-RNA covalent complex, S-adenosyl-L-homocysteine and pH are likely to influence the extent of m5C formation and the rate of release of methylated RNA from RNA:m5C methyltransferases. Metabolite-induced covalent complexes could plausibly affect the processing and function of m5C-containing RNAs
metabolism
during the maturation of the cytoplasmic tRNALeu(CAA), an m5C34 modification is also installed by the multisite-specific NSUN2 (cf. EC 2.1.1.202)
metabolism
during the maturation of the cytoplasmic tRNALeu(CAA), an m5C34 modification is also installed by the multisite-specific NSUN2 (cf. EC 2.1.1.202)
metabolism
the nucleolus, where NSUN2 resides, can act as a stress sensor. Nucleophosmin (NPMI) is a marker for nucleolar stress, and a rapid, strong down-regulation of both NPMI and NSUN2 is observed upon arsenite treatment. Additional NSUN family members residing in the mitochondria (NSUN3, NSUN4) and cytoplasm (NSUN6) are similarly repressed in response to arsenite stress
physiological function
specific modification of cytosine34 in the intron-containing yeast pre-tRNALeu(CAA)
physiological function
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NSUN2 encodes a methyltransferase that catalyzes the intron-dependent formation of 5-methylcytosine at C34 of tRNA-leu(CAA). It also functions in spindle assembly during mitosis as well as chromosome segregation
physiological function
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NSUN2 encodes a methyltransferase that catalyzes the intron-dependent formation of 5-methylcytosine at C34 of tRNA-leu(CAA). It also functions in spindle assembly during mitosis as well as chromosome segregation
physiological function
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methylation by NSun2 inhibits the processing of pri-miR- 125b2 into pre-miR-125b2, decreases the cleavage of pre-miR-125b2 into miR-125, and attenuates the recruitment of RISC by miR-125, thereby repressing the function of miR-125b in silencing gene expression
physiological function
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NSUN2 (NOP2/Sun domain family, member 2) is a NOL1/NOP2/SUN domain-containing tRNA (cytosine-5-)-methyltransferase. Nonessential tRNA modifications by methyltransferases are evolutionarily conserved and have been reported to stabilize mature tRNA molecules and prevent rapid tRNA decay. The tRNA modifying enzyme NSUN2 is a mammalian orthologues of yeast Trm4, which is required for protecting tRNA against tRNA decay. Enzyme NUSN2 is not a critical regulator of cancer cell growth
physiological function
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NSun2 catalyzes the formation of cytosine-5 methylation in several tRNAs in vivo in tissues, including skin, liver, and testis. Functionally, the cytosine-5 methylation posttranscriptional modification influences translation rates, as well as correct RNA folding and stability. The mouse enzyme NSun2 is a component of the chromatoid body, NSun2 is essential for germ cell differentiation in the mouse testis. Cytosine-5 tRNA methyltransferases are dispensable for the spermatogonium and early spermatocytes
physiological function
cytosine-5 RNA methylation links protein synthesis to cell metabolism. NSUN2 functions in the cell cycle to adapt dynamic protein synthesis in response to stress. Cytosine-5 RNA methylation is a metabolic sensor of external stress. NSUN2 regulates cell cycle phases and global protein synthesis during the cellular stress response. Cell stress causes a strong but temporary reduction of protein synthesis, which is attenuated by loss of NSUN2. In response to stress, the percentage of NSUN2+/+ cells decreased in the G1/G0-phase but increased in the S-phase and G2/M-phase of the cell cycle. In contrast, the cell cycle progression of NSUN2-/- cells remained stable, indicating that NSUN2-/- cells fail to adapt the cell cycle phases to the stress stimulus. A tight regulation of global protein synthesis might be needed to avoid accumulation of proteins during cell cycle arrest and repair. Dynamic changes of site-specific m5C levels require NSUN2. Site-specific tRNA methylation determines tRNA-derived fragments (tRFs) biogenesis in response to oxidative stress
physiological function
in human mitochondria, the AUA codon encodes methionine via a mitochondrial transfer RNA for methionine (mt-tRNAMet) that contains 5-formylcytidine (f5C) at the first position of the anticodon (position 34). f5C34 is required for deciphering the AUA codon during protein synthesis. Biogenesis of f5C34 is initiated by S-adenosylmethionine (AdoMet)-dependent methylation catalyzed by NSUN3, a methyltransferase in mitochondria. NSUN3 methylase initiates 5-formylcytidine biogenesis in human mitochondrial tRNAMet. NSUN3 is essential for f5C34 formation
physiological function
mutations in two (cytosine-5) RNA methyltransferase NSun2 impact the accumulation of mobile element-derived sequences and DNA repeat integrity in Drosophila melanogaster. NSun2 function affects mobile element expression and genome integrity in a heat shock-independent fashion. Reduced tRNA stability in mutants indicates that tRNA-dependent processes affected mobile element expression and DNA repeat stability
physiological function
NSun2 protein is a highly conserved (cytosine-5) methyltransferases that methylate specific tRNAs instead of genomic DNA. NSun2 function affects repeat elements in a heat shock-independent fashion. NSun2, is an RCMT targeting the majority of tRNAs
physiological function
NSUN3 is a mitochondrial tRNA m5C methyltransferase that specifically targets the wobble position (C34) of mt-tRNAMet. Mt-tRNAMet-C34 is almost fully modified in vivo, and, although bisulfite and reduced bisulfite sequencing analyses indicate the presence of some m5C at this position, the majority undergoes further oxidation by ALKBH1 to generate 5-formylcytosine (f5C), structures of modified nucleotides at position 34 and the modification pathway. 5-Formylcytosine (f5C) has a well-established role in expanding codon recognition by mt-tRNAMet during mitochondrial translation. Modification of mt-tRNAMet by NSUN3 occurs in the mitochondria
physiological function
NSUN3 is a mitochondrial tRNA m5C methyltransferase that specifically targets the wobble position (C34) of mt-tRNAMet. The wobble base modification(s) installed by NSUN3 and ALKBH1 likely serve to expand codon recognition by mt-tRNAMet, enabling it to fulfil these diverse functions. Mt-tRNAMet-C34 is almost fully modified in vivo, and, although bisulfite and reduced bisulfite sequencing analyses indicate the presence of some m5C at this position, the majority undergoes further oxidation by ALKBH1 to generate 5-formylcytosine (f5C), structures of modified nucleotides at position 34 and the modification pathway. 5-Formylcytosine (f5C) has a well-established role in expanding codon recognition by mt-tRNAMet during mitochondrial translation. Modification of mt-tRNAMet by NSUN3 occurs in the mitochondria
additional information
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four active-site residues critical for Nsun2-mediated tRNA methylation are also required for the formation of the denaturant-resistant complexes with m5C-containing RNA
additional information
catalytic mechanism of the enzyme, comparison of NSUN family enzymes, overview. The NSUN family enzymes use the cysteine located in amino acid motif VI for the nucleophilic attack on carbon 6 of the target cytosine in RNA. In all seven human NSUN variants, the catalytic cysteine is preceded by threonine. Hydrogen bonding with the backbone carbonyl of proline and the aspartate side chain in motif IV orients the base in the active site and assists bond formation by transient protonation of the endocyclic N3 of cytidine. The activated nucleobase then accepts a methyl group from the properly positioned SAM cofactor, resulting in the formation of a carbon-carbon bond and generation of S-adenosylhomocysteine (SAH). To complete the reaction, the covalently bound methylated RNA has to be released from the protein. This elimination is assisted by the cysteine located in motif IV of NSUN proteins. This cysteine is located next to the conserved proline and acts as a base to deprotonate the tetrahedral carbon and initiate the elimination reaction that restores the unsaturated m5C heterocycle
additional information
catalytic mechanism of the enzyme, comparison of NSUN family enzymes, overview. The NSUN family enzymes use the cysteine located in amino acid motif VI for the nucleophilic attack on carbon 6 of the target cytosine in RNA. In all seven human NSUN variants, the catalytic cysteine is preceded by threonine. Hydrogen bonding with the backbone carbonyl of proline and the aspartate side chain in motif IV orients the base in the active site and assists bond formation by transient protonation of the endocyclic N3 of cytidine. The activated nucleobase then accepts a methyl group from the properly positioned SAM cofactor, resulting in the formation of a carbon-carbon bond and generation of S-adenosylhomocysteine (SAH). To complete the reaction, the covalently bound methylated RNA has to be released from the protein. This elimination is assisted by the cysteine located in motif IV of NSUN proteins. This cysteine is located next to the conserved proline and acts as a base to deprotonate the tetrahedral carbon and initiate the elimination reaction that restores the unsaturated m5C heterocycle
