NSUN2

RNA cytosine-5 methyltransferase, the human orthologue of yeast Trm4, and the enzyme responsible for most 5-methylcytosine in human RNA. NSUN2 uses S-adenosyl-L-methionine and a catalytic cysteine to methylate cytosines in transfer RNA: the wobble base C34 of intron-containing pre-tRNA-Leu(CAA), and C47-C50 in the variable loop of many cytoplasmic tRNAs. It is imported into the mitochondrial matrix, where it makes m5C at positions 48-50 of several mitochondrial tRNAs, and it is the sole enzyme that methylates C69 of the vault RNA VTRNA1.1, thereby directing its processing into small vault RNAs. The methylation it deposits protects tRNAs from stress-induced endonucleolytic cleavage, and loss of the enzyme alters translation, tRNA-fragment production and the differentiation of skin, hair follicle and neural stem cells; biallelic loss-of-function variants cause autosomal-recessive intellectual disability and a Dubowitz-like syndrome. NSUN2 is predominantly nuclear and nucleolar, with cytoplasmic and mitochondrial pools, and it has been detected in secreted exosomes. NSUN2 also methylates messenger RNA, and m5C in mRNA has been linked to nuclear export via ALYREF and to transcript stabilisation via YBX1; this substrate class is genuinely contested, because the mapping methods used to locate mRNA m5C sites - bisulfite sequencing, Aza-IP and miCLIP - agree poorly with one another, mRNA structure generates false-positive bisulfite signals, and the modification occurs at roughly one in several thousand cytosines, which leaves it unclear how the proposed reader proteins discriminate modified transcripts.

Disorders

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