Literature summary for 2.1.1.203 extracted from

Gkatza, N.A.; Castro, C.; Harvey, R.F.; Heiss, M.; Popis, M.C.; Blanco, S.; Borneloev, S.; Sajini, A.A.; Gleeson, J.G.; Griffin, J.L.; West, J.A.; Kellner, S.; Willis, A.E.; Dietmann, S.; Frye, M.
Cytosine-5 RNA methylation links protein synthesis to cell metabolism (2019), PLoS Biol., 17, e3000297 .

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Protein Variants

Protein Variants	Comment	Organism
K190M	site-directed mutagenesis, catalytically inactive mutant	Homo sapiens
additional information	generation of enzyme depeleted NSUN2-/- cells. Rescue for loss of NSUN2 by reexpressing the wild-type or enzymatic dead protein. The number of m5C per tRNA in all tRNAs or tRNA leucine is quantified by mass spectrometry in NSUN2-/- cells reexpressing wild-type NSUN2, the catalytically inactive NSUN2 K190M mutant, or the empty vector control. Reexpression of NSUN2 significantly restores 525 methylation sites when compared to the empty vector control and 431 sites when compared to K190M-overexpressing cells	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
nucleolus	-	Homo sapiens	5730	-

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
additional information	Homo sapiens	levels of m5C changes site-specifically and dynamically in response to oxidative stress. All individual m5C sites showing significantly different methylation levels in NSUN2-rescued cells after 2 or 4 hours of stress. Methylation levels within the same tRNA molecule are independent from each other	?	-	-
S-adenosyl-L-methionine + cytosine34 in tRNA precursor	Homo sapiens	-	S-adenosyl-L-homocysteine + 5-methylcytosine34 in tRNA precursor	-	?
S-adenosyl-L-methionine + cytosine34 in tRNALeu(CAG) precursor	Homo sapiens	-	S-adenosyl-L-homocysteine + 5-methylcytosine34 in tRNALeu(CAG) precursor	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q08J23	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
additional information	levels of m5C changes site-specifically and dynamically in response to oxidative stress. All individual m5C sites showing significantly different methylation levels in NSUN2-rescued cells after 2 or 4 hours of stress. Methylation levels within the same tRNA molecule are independent from each other	Homo sapiens	?	-	-
additional information	NSUN2-methylated tRNA sites are located in the anticodon loop (C34) and the VL (C46, C47), number of m5C per tRNA in all tRNAs or tRNA leucine, mass spectrometry, overview	Homo sapiens	?	-	-
S-adenosyl-L-methionine + cytosine34 in tRNA precursor	-	Homo sapiens	S-adenosyl-L-homocysteine + 5-methylcytosine34 in tRNA precursor	-	?
S-adenosyl-L-methionine + cytosine34 in tRNALeu(CAG) precursor	-	Homo sapiens	S-adenosyl-L-homocysteine + 5-methylcytosine34 in tRNALeu(CAG) precursor	-	?

Synonyms

Synonyms	Comment	Organism
NSUN2	-	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
S-adenosyl-L-methionine	-	Homo sapiens

Expression

Organism	Comment	Expression
Homo sapiens	expression of NSUN2 and at least three of its m5C RNA methyltransferase family members are repressed in response to oxidative stress. Rapid and strong downregulation of NSUN2 upon arsenite treatment	down

General Information

General Information	Comment	Organism
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	Homo sapiens
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	Homo sapiens
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	Homo sapiens

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Release 2023.1 (January 2023)