| Structural highlights
Disease
NSUN2_HUMAN Autosomal recessive non-syndromic intellectual disability;Dubowitz syndrome. The disease is caused by variants affecting the gene represented in this entry.
Function
NSUN2_HUMAN RNA cytosine C(5)-methyltransferase that methylates cytosine to 5-methylcytosine (m5C) in various RNAs, such as tRNAs, mRNAs and some long non-coding RNAs (lncRNAs) (PubMed:17071714, PubMed:22995836, PubMed:31199786, PubMed:31358969). Involved in various processes, such as epidermal stem cell differentiation, testis differentiation and maternal to zygotic transition during early development: acts by increasing protein synthesis; cytosine C(5)-methylation promoting tRNA stability and preventing mRNA decay (PubMed:31199786). Methylates cytosine to 5-methylcytosine (m5C) at positions 34 and 48 of intron-containing tRNA(Leu)(CAA) precursors, and at positions 48, 49 and 50 of tRNA(Gly)(GCC) precursors (PubMed:17071714, PubMed:22995836, PubMed:31199786). tRNA methylation is required generation of RNA fragments derived from tRNAs (tRFs) (PubMed:31199786). Also mediates C(5)-methylation of mitochondrial tRNAs (PubMed:31276587). Catalyzes cytosine C(5)-methylation of mRNAs, leading to stabilize them and prevent mRNA decay: mRNA stabilization involves YBX1 that specifically recognizes and binds m5C-modified transcripts (PubMed:22395603, PubMed:31358969, PubMed:34556860). Cytosine C(5)-methylation of mRNAs also regulates mRNA export: methylated transcripts are specifically recognized by THOC4/ALYREF, which mediates mRNA nucleo-cytoplasmic shuttling (PubMed:28418038). Also mediates cytosine C(5)-methylation of non-coding RNAs, such as vault RNAs (vtRNAs), promoting their processing into regulatory small RNAs (PubMed:23871666). Cytosine C(5)-methylation of vtRNA VTRNA1.1 promotes its processing into small-vault RNA4 (svRNA4) and regulates epidermal differentiation (PubMed:31186410). May act downstream of Myc to regulate epidermal cell growth and proliferation (By similarity). Required for proper spindle assembly and chromosome segregation, independently of its methyltransferase activity (PubMed:19596847).[UniProtKB:Q1HFZ0][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
The human RNA m(5)C methyltransferase NSUN2 catalyzes site-specific cytosine methylation across diverse RNA substrates and thereby regulates a wide range of biological and physiological processes. However, the molecular basis by which NSUN2 achieves broad substrate recognition while maintaining catalytic specificity has remained unclear. Here, we determine structures of human NSUN2 in both substrate-free and substrate-bound states using X-ray crystallography and cryo-electron microscopy. Structures of NSUN2 in complex with multiple tRNA substrates reveal a structure-first, sequence-tolerant strategy in which NSUN2 actively remodels tRNA architecture, exposing the buried target cytosine and positioning it within the catalytic pocket for methyl transfer. This recognition strategy enables NSUN2 to accommodate diverse tRNA substrates through a largely conserved interaction interface. Together, our findings define the molecular principles underlying NSUN2-mediated RNA m(5)C modification.
Structure-driven RNA remodeling underlies broad substrate recognition by NSUN2.,Hu Q, Yang W, Yu Y, Yi R, Zhang Y, Duan L, Li F, Zhang K, Gong Q, Li S Sci China Life Sci. 2026 May 26. doi: 10.1007/s11427-026-3373-3. PMID:42258135[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Brzezicha B, Schmidt M, Makalowska I, Jarmolowski A, Pienkowska J, Szweykowska-Kulinska Z. Identification of human tRNA:m5C methyltransferase catalysing intron-dependent m5C formation in the first position of the anticodon of the pre-tRNA Leu (CAA). Nucleic Acids Res. 2006;34(20):6034-43. PMID:17071714 doi:10.1093/nar/gkl765
- ↑ Hussain S, Benavente SB, Nascimento E, Dragoni I, Kurowski A, Gillich A, Humphreys P, Frye M. The nucleolar RNA methyltransferase Misu (NSun2) is required for mitotic spindle stability. J Cell Biol. 2009 Jul 13;186(1):27-40. PMID:19596847 doi:10.1083/jcb.200810180
- ↑ Zhang X, Liu Z, Yi J, Tang H, Xing J, Yu M, Tong T, Shang Y, Gorospe M, Wang W. The tRNA methyltransferase NSun2 stabilizes p16INK⁴ mRNA by methylating the 3'-untranslated region of p16. Nat Commun. 2012 Mar 6;3:712. PMID:22395603 doi:10.1038/ncomms1692
- ↑ Auxilien S, Guérineau V, Szweykowska-Kulińska Z, Golinelli-Pimpaneau B. The human tRNA m (5) C methyltransferase Misu is multisite-specific. RNA Biol. 2012 Nov;9(11):1331-8. PMID:22995836 doi:10.4161/rna.22180
- ↑ Hussain S, Sajini AA, Blanco S, Dietmann S, Lombard P, Sugimoto Y, Paramor M, Gleeson JG, Odom DT, Ule J, Frye M. NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs. Cell Rep. 2013 Jul 25;4(2):255-61. PMID:23871666 doi:10.1016/j.celrep.2013.06.029
- ↑ Yang X, Yang Y, Sun BF, Chen YS, Xu JW, Lai WY, Li A, Wang X, Bhattarai DP, Xiao W, Sun HY, Zhu Q, Ma HL, Adhikari S, Sun M, Hao YJ, Zhang B, Huang CM, Huang N, Jiang GB, Zhao YL, Wang HL, Sun YP, Yang YG. 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m(5)C reader. Cell Res. 2017 May;27(5):606-625. doi: 10.1038/cr.2017.55. Epub 2017 Apr 18. PMID:28418038 doi:https://dx.doi.org/10.1038/cr.2017.55
- ↑ Sajini AA, Choudhury NR, Wagner RE, Bornelov S, Selmi T, Spanos C, Dietmann S, Rappsilber J, Michlewski G, Frye M. Loss of 5-methylcytosine alters the biogenesis of vault-derived small RNAs to coordinate epidermal differentiation. Nat Commun. 2019 Jun 11;10(1):2550. doi: 10.1038/s41467-019-10020-7. PMID:31186410 doi:https://dx.doi.org/10.1038/s41467-019-10020-7
- ↑ Gkatza NA, Castro C, Harvey RF, Heiss M, Popis MC, Blanco S, Bornelov S, Sajini AA, Gleeson JG, Griffin JL, West JA, Kellner S, Willis AE, Dietmann S, Frye M. Cytosine-5 RNA methylation links protein synthesis to cell metabolism. PLoS Biol. 2019 Jun 14;17(6):e3000297. doi: 10.1371/journal.pbio.3000297. , eCollection 2019 Jun. PMID:31199786 doi:https://dx.doi.org/10.1371/journal.pbio.3000297
- ↑ Van Haute L, Lee SY, McCann BJ, Powell CA, Bansal D, Vasiliauskaite L, Garone C, Shin S, Kim JS, Frye M, Gleeson JG, Miska EA, Rhee HW, Minczuk M. NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs. Nucleic Acids Res. 2019 Sep 19;47(16):8720-8733. doi: 10.1093/nar/gkz559. PMID:31276587 doi:https://dx.doi.org/10.1093/nar/gkz559
- ↑ Chen X, Li A, Sun BF, Yang Y, Han YN, Yuan X, Chen RX, Wei WS, Liu Y, Gao CC, Chen YS, Zhang M, Ma XD, Liu ZW, Luo JH, Lyu C, Wang HL, Ma J, Zhao YL, Zhou FJ, Huang Y, Xie D, Yang YG. 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nature cell biology. 2019 Aug 1. doi: 10.1038/s41556-019-0361-y. PMID: 31358969.
- ↑ Dai W, Li A, Yu NJ, Nguyen T, Leach RW, Wuhr M, Kleiner RE. Activity-based RNA-modifying enzyme probing reveals DUS3L-mediated dihydrouridylation. Nat Chem Biol. 2021 Nov;17(11):1178-1187. doi: 10.1038/s41589-021-00874-8. Epub , 2021 Sep 23. PMID:34556860 doi:https://dx.doi.org/10.1038/s41589-021-00874-8
- ↑ Hu Q, Yang W, Yu Y, Yi R, Zhang Y, Duan L, Li F, Zhang K, Gong Q, Li S. Structure-driven RNA remodeling underlies broad substrate recognition by NSUN2. Sci China Life Sci. 2026 May 26. PMID:42258135 doi:10.1007/s11427-026-3373-3
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