Affinage

NSUN2

RNA cytosine C(5)-methyltransferase NSUN2 · UniProt Q08J23

Length
767 aa
Mass
86.5 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NSUN2 is a SAM-dependent RNA:m5C methyltransferase that post-transcriptionally controls gene expression by writing 5-methylcytosine onto tRNAs, mRNAs, mitochondrial tRNAs, and noncoding RNAs to govern proliferation, differentiation, and stress responses (PMID:10445884, PMID:28418038). It uses a dual-cysteine catalytic mechanism that forms a transient covalent enzyme–RNA intermediate disassembled by S-adenosylhomocysteine release, with the catalytic cysteines (e.g., C271/C321) and the SAM-binding pocket required for activity (PMID:25375641, PMID:37909922, PMID:40691844). On tRNAs it methylates the variable-arm/anticodon region (positions 34, 40, 48–50), and its loss—non-redundant with DNMT2—reduces tRNA stability and codon-specific translation of, for example, glycine and valine codons, with downstream effects on neuronal function and glycolytic enzyme synthesis (PMID:10445884, PMID:22995836, PMID:22885326, PMID:34389722, PMID:40855521). On mRNAs NSUN2-deposited m5C is interpreted by sequence-specific reader proteins: ALYREF promotes nuclear export of methylated transcripts, while YBX1 stabilizes targets and enhances their translation, mechanisms exploited across cancers (KRT13, QSOX1, SLC7A11, FSP1, PRKACA) (PMID:28418038, PMID:33093178, PMID:35280737, PMID:38042059, PMID:39990213, PMID:40691844). Through methylation of specific transcripts NSUN2 tunes cell-cycle regulators (stabilizing p16, repressing p27, enhancing CDK1) and immune/antiviral effectors, methylating IL-17A to drive Th17 differentiation while destabilizing IRF3 to dampen type I interferon and modifying viral RNAs such as HBV (PMID:22395603, PMID:26687548, PMID:26391950, PMID:28919411, PMID:36792629, PMID:36748584, PMID:38048324). NSUN2 also localizes to nucleoli, the mitotic spindle, and the mitochondrial matrix, where it stabilizes spindle microtubules via NuSAP recruitment and methylates mitochondrial tRNAs (PMID:19596847, PMID:31276587, PMID:31287866). Its activity is heavily regulated by post-translational and metabolic inputs: inhibitory Aurora-B phosphorylation at Ser139, SUMO-2/3-mediated stabilization and nuclear import, STUB1-mediated ubiquitination and degradation, activating lactylation (K508), and direct glucose binding at the N-terminus that promotes oligomerization and SAM binding (PMID:17215513, PMID:34504059, PMID:37586363, PMID:39565212, PMID:39453812, PMID:39742570). NSUN2 was first defined as a Myc target controlling keratinocyte proliferation and is recurrently co-opted in cancers and metabolic/ferroptosis programs (PMID:16713953, PMID:37586363, PMID:40691844).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Established the founding enzymatic identity of the NSUN2 family as a SAM-dependent tRNA m5C methyltransferase with multisite specificity.

    Evidence Recombinant yeast Trm4 in vitro methylation of tRNA transcripts plus gene disruption eliminating all tRNA m5C

    PMID:10445884

    Open questions at the time
    • Done in yeast ortholog; human enzyme not yet characterized
    • mRNA and noncoding RNA substrates not addressed
  2. 2006 Medium

    Placed NSUN2 downstream of Myc as a proliferation effector and revealed dynamic, cell-cycle-coupled subcellular localization.

    Evidence RNAi in keratinocytes, immunofluorescence, and xenograft assays

    PMID:16713953

    Open questions at the time
    • RNA substrates mediating the proliferation phenotype not defined
    • Mechanism of cytoplasmic/spindle redistribution unknown
  3. 2007 High

    Identified the first regulatory PTM controlling NSUN2 activity, linking mitotic kinase signaling to methyltransferase output.

    Evidence In vitro kinase and methylation assays with phospho-mimic/deficient mutants and Co-IP with NPM1

    PMID:17215513

    Open questions at the time
    • Physiological substrates regulated by Ser139 phosphorylation not mapped
    • Phosphatase reversing the mark unknown
  4. 2009 High

    Defined a non-catalytic structural role at the mitotic spindle, expanding NSUN2 beyond RNA methylation into chromosome segregation.

    Evidence Live/fixed imaging, siRNA depletion, spindle assembly and NuSAP recruitment assays

    PMID:19596847

    Open questions at the time
    • Whether spindle role requires catalytic activity unresolved
    • Role of associated 18S rRNA mechanistically unclear
  5. 2010 High

    Provided the structural basis for AdoMet entry and tRNA recognition, rationalizing catalytic and stability-critical residues.

    Evidence X-ray crystallography of archaeal ortholog apo and sinefungin-bound forms with activity validation

    PMID:20600111

    Open questions at the time
    • Human NSUN2 structure not solved
    • No structure with mRNA or full-length tRNA substrate
  6. 2012 High

    Demonstrated non-redundant tRNA target specificity between NSUN2 and DNMT2 and its requirement for protein synthesis and development.

    Evidence Double-knockout mice with synthetic lethality, tRNA methylation analysis, and protein synthesis measurement

    PMID:22885326 PMID:22995836

    Open questions at the time
    • Codon-level translational consequences not yet mapped
    • Tissue-specific tRNA target hierarchy unclear
  7. 2012 High

    Extended NSUN2 substrate scope to mRNA, showing m5C stabilizes target transcripts by blocking decay machineries.

    Evidence In vitro methylation, mRNA half-life and reporter assays, and RIP for HuR/AUF1/Ago2 on p16 mRNA

    PMID:22395603

    Open questions at the time
    • Reader protein for mRNA m5C not yet identified
    • Transcriptome-wide mRNA target set unknown at this stage
  8. 2014 High

    Mechanistically resolved the dual-cysteine covalent intermediate and extended NSUN2 function to miRNA biogenesis and vault RNA processing.

    Evidence Covalent complex biochemistry with active-site mutagenesis; miCLIP/bisulfite-seq and Ago-IP on vault RNAs and miR-125b processing assays

    PMID:23871666 PMID:25047833 PMID:25375641

    Open questions at the time
    • In vivo prevalence of covalent intermediate unclear
    • How methylation kinetics control noncoding RNA fate not quantified
  9. 2015 High

    Connected NSUN2 mRNA methylation to translational control of cell-cycle regulators, integrating it into senescence programs.

    Evidence In vitro methylation at defined cytosines, translation reporter and polysome assays, KD/OE on p27 and CDK1

    PMID:26391950 PMID:26687548

    Open questions at the time
    • How m5C exerts opposite effects (repress p27, enhance CDK1) mechanistically unclear
    • Reader proteins for these targets not defined here
  10. 2017 High

    Identified ALYREF as the first m5C mRNA reader, defining a writer–reader axis coupling methylation to nuclear export.

    Evidence Transcriptome-wide bisulfite-seq, binding studies, fractionation, and catalytic-mutant rescue of export defects

    PMID:28418038

    Open questions at the time
    • Determinants of ALYREF sequence/structure preference incomplete
    • Crosstalk with other modifications only partly addressed
  11. 2019 High

    Established NSUN2 import into the mitochondrial matrix and methylation of mitochondrial tRNAs across multiple genetic models.

    Evidence BioID proximity labeling, KO mice, patient fibroblasts, CRISPR KO, MS modification mapping, and in vitro reconstitution

    PMID:31276587 PMID:31287866

    Open questions at the time
    • Functional consequence for OXPHOS modest/cell-type dependent
    • Import machinery and dual-targeting signals not defined
  12. 2017 Medium

    Linked NSUN2 mRNA methylation to vascular inflammation and immune effector translation, with metabolic activation via suppressed Aurora-B phosphorylation.

    Evidence In vitro/in-cell methylation, NSUN2-KO rats, and reporter/bisulfite assays on ICAM-1, SHC, IL-17A, and p21

    PMID:26838785 PMID:26992231 PMID:28247949 PMID:28919411

    Open questions at the time
    • Pathway placements partly correlative
    • Reader proteins for these inflammatory targets not all identified
  13. 2022 Medium

    Defined YBX1 as a stabilizing m5C reader and showed catalytic-activity dependence of NSUN2 oncogenic function across multiple cancers.

    Evidence RNA-bisulfite-seq, RIP/domain mapping, catalytic-dead mutant rescue on KRT13, GRB2, QSOX1, SLC7A11, FSP1, PRKACA

    PMID:34345012 PMID:35280737 PMID:37161388 PMID:38042059 PMID:39990213 PMID:40691844

    Open questions at the time
    • Reader selection rules (ALYREF vs YBX1 vs LIN28B) not unified
    • Most axes from single labs without cross-validation
  14. 2023 High

    Revealed extensive regulation of NSUN2 stability and activity by ubiquitination, SUMOylation, lncRNA shielding, lactylation, and direct glucose binding.

    Evidence Co-IP, ubiquitination/lactylation site mutagenesis, glucose- and SAM-binding assays, oligomerization, lncRNA pulldowns

    PMID:34504059 PMID:37037818 PMID:37586363 PMID:38769664 PMID:39453812 PMID:39565212 PMID:39742570

    Open questions at the time
    • Hierarchy and crosstalk among PTMs not integrated
    • Stoichiometry and contextual triggers of each modification unclear
  15. 2023 Medium

    Positioned NSUN2 as a regulator of antiviral immunity and a host factor for viral RNAs through m5C-dependent transcript fate.

    Evidence KO cells/mice, bisulfite-seq and m5C-site mutation, mRNA decay assays on IRF3 and HBV RNA in infection models

    PMID:36748584 PMID:38048324

    Open questions at the time
    • Whether IRF3 destabilization generalizes across cell types unclear
    • Reader for destabilizing m5C not defined
  16. 2024 High

    Connected NSUN2 to tissue physiology in heart, brain, gut immunity, and ferroptosis/metabolism through specific m5C target programs.

    Evidence Conditional/cardiac/T-cell KO mice, ChIP for RORγt and H3K18la, ribosome and polysome profiling on PRKACA, IL17, tRNAVal, GCLC, GPX4

    PMID:34389722 PMID:36357715 PMID:36792629 PMID:38769664 PMID:39453812 PMID:39742570 PMID:39990213 PMID:40855521

    Open questions at the time
    • Tissue-specific target selection mechanisms incomplete
    • Causal relationships in disease models partly correlative

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NSUN2 selects between catalytic and non-catalytic roles and chooses among competing m5C reader outcomes (export vs stabilization vs decay) in a given cell remains unresolved.
  • No unified model of reader recruitment specificity
  • No human full-length structure with substrate
  • Integration of metabolic/PTM inputs into target choice undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 6 GO:0003723 RNA binding 4 GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005730 nucleolus 3 GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1640170 Cell Cycle 3 R-HSA-168256 Immune System 3
Partners
ALYREFLIN28BNAA10NPM1NUSAPSTUB1SUMO2YBX1

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Yeast Trm4 (ortholog of NSUN2, encoded by ORF YBL024w) is an S-adenosyl-L-methionine-dependent tRNA:m5C-methyltransferase that methylates cytosine at positions 34, 40, 48, and 49 in multiple yeast tRNAs and pre-tRNAs; disruption of the gene eliminates all tRNA m5C methylation in yeast. Recombinant protein expression and purification, in vitro methylation assay with T7 tRNA transcripts, gene disruption in yeast RNA (New York, N.Y.) High 10445884
2006 Misu/NSUN2 is a direct transcriptional target of Myc; its nucleolar localization depends on RNA polymerase III transcripts; knockdown blocks Myc-induced keratinocyte proliferation and reduces nucleolar size; it is redistributed to cytoplasmic vesicles in G2 and to the mitotic spindle. RNAi knockdown in keratinocytes, immunofluorescence for localization, siRNA in xenograft tumor model, cell-cycle analysis Current biology : CB Medium 16713953
2007 Aurora-B kinase phosphorylates NSUN2 at Ser139 during mitosis, inhibiting its methyltransferase activity and disrupting its association with nucleolar protein NPM1/nucleophosmin; Aurora-B inhibition restores NSUN2–NPM1 association even during mitosis. In vitro kinase assay, in vitro methylation assay, co-immunoprecipitation, phosphorylation-mimic and phospho-deficient NSUN2 mutants Molecular biology of the cell High 17215513
2009 Misu/NSUN2 translocates from nucleoli in interphase to the mitotic spindle as an RNA-protein complex containing 18S rRNA; its depletion causes multipolar spindles, chromosome missegregation, aneuploidy, and cell death; NSUN2 recruits NuSAP to the spindle for microtubule stabilization. Immunofluorescence live/fixed imaging, siRNA depletion, spindle assembly assay, RNA–protein complex characterization The Journal of cell biology High 19596847
2010 Crystal structure of archaeal Trm4 (NSUN2 ortholog from Methanocaldococcus jannaschii, MJ0026) complexed with sinefungin (AdoMet analog) revealed a negatively charged binding pocket near helix α8 controlling AdoMet entry, and a large positively charged surface for tRNA binding; the structure rationalizes conserved residues essential for catalysis and stability. X-ray crystallography at 1.27 Å (apo) and 2.3 Å (sinefungin complex), in vitro methyltransferase activity assay Journal of molecular biology High 20600111
2011 NSun2/Misu is required to balance epidermal stem cell self-renewal and differentiation; depletion results in enhanced quiescence and aberrant lineage commitment, placing NSun2-mediated RNA methylation as a post-transcriptional regulator of stem cell fate in skin. Conditional depletion in mouse skin, immunofluorescence, stem cell functional assays PLoS genetics Medium 22144916
2012 NSUN2 methylates the 3′-UTR of p16(INK4) mRNA at position A988 in vitro and in cells; this methylation stabilizes p16 mRNA by preventing association with HuR, AUF1, and Ago2/RISC, and prevents recruitment to processing bodies; NSun2 knockdown shortens p16 mRNA half-life. In vitro methylation assay, mRNA half-life measurement, chimeric reporter assay, RIP (HuR/AUF1/Ago2), siRNA knockdown Nature communications High 22395603
2012 The human tRNA methyltransferase Misu/NSUN2 methylates position 48 in tRNA-Leu(CAA) (with or without intron) and positions 48, 49, and 50 in tRNA-Gly2(GCC) in vitro, demonstrating multisite specificity. Recombinant protein expression and purification in E. coli, in vitro methylation assay with multiple tRNA substrates RNA biology High 22995836
2012 Disruption of both Dnmt2 and NSun2 tRNA methyltransferases in mice causes synthetic lethality with underdeveloped phenotype and impaired differentiation; Dnmt2 and NSun2 have complementary, non-overlapping tRNA target-site specificities; loss of both reduces steady-state levels of unmethylated tRNAs and overall protein synthesis rates. Double-knockout mouse model, tRNA methylation analysis, protein synthesis rate measurement Nature structural & molecular biology High 22885326
2013 NSun2 methylates cytosine-5 at six positions in vault noncoding RNAs; loss of NSun2-mediated m5C in vault RNAs causes their aberrant processing into Argonaute-associated small RNA fragments that function as microRNAs, as shown in patient cells lacking NSun2. miCLIP (individual-nucleotide-resolution CLIP), RNA bisulfite sequencing, Argonaute immunoprecipitation, patient cells Cell reports High 23871666
2013 NSun2 is a component of the chromatoid body in mouse testes; NSun2 knockout blocks meiotic progression at the pachytene stage; simultaneous deletion of NSun2 and Dnmt2 decreases abundance of specific methylated tRNAs and confirms non-redundant roles in spermatogonial cells and Sertoli cells. Knockout mice, immunofluorescence, tRNA methylation analysis, histology Molecular and cellular biology Medium 23401851
2014 NSun2 methylates primary (pri-miR-125b), precursor (pre-miR-125b), and mature miR-125b in vitro and in vivo; methylation inhibits processing of pri-miR-125b2 into pre-miR-125b2, decreases cleavage to mature miR-125, and attenuates RISC recruitment, thereby repressing miR-125b function. In vitro methylation assay, pri/pre-miRNA processing assay, RISC loading assay, in vivo methylation Molecular and cellular biology High 25047833
2014 Trm4 (yeast NSUN2 ortholog) and mammalian Nsun2 form covalent complexes with previously methylated (m5C-containing) RNA in a manner requiring S-adenosylhomocysteine (AdoHcy); four active-site residues critical for tRNA methylation are also required for this covalent complex formation; removal of AdoHcy disassembles the complexes. Biochemical covalent complex assay with recombinant proteins, active-site mutagenesis, metabolite titration experiments Biochemistry High 25375641
2015 NSun2 methylates the 5′-UTR of p27 mRNA at cytosine C64 in vitro and in cells, repressing p27 translation; NSun2 also enhances CDK1 mRNA translation through methylation; knockdown of NSun2 elevates p27, reduces CDK1, and accelerates replicative senescence. In vitro methylation assay, translation reporter assay, RNAi knockdown, protein level analysis Aging High 26687548
2015 NSun2 methylates CDK1 mRNA in vitro and in cells; this methylation enhances CDK1 translation without altering CDK1 mRNA levels; NSun2-mediated CDK1 upregulation drives cell cycle progression. In vitro methylation assay, overexpression/knockdown, CDK1 translation assay (polysome analysis), cell cycle analysis Molecular and cellular biology High 26391950
2016 NSun2 methylates ICAM-1 mRNA and promotes its translation, increasing leukocyte adhesion to endothelial cells; TNF-α or homocysteine activates NSun2 methyltransferase activity by suppressing Aurora-B-mediated phosphorylation of NSun2; NSun2-deficient rats show decreased ICAM-1 induction and impaired allograft arteriosclerosis. In vitro methylation assay, in-cell methylation assay, NSun2-knockout rat model, vascular inflammation assay Circulation research High 26838785
2016 NSun2 methylates SHC mRNA in vitro and in cells, enhancing translation of all three SHC proteins (p66SHC, p52SHC, p46SHC), which increases ROS and activates p38MAPK to accelerate oxidative stress- and high-glucose-induced HUVEC senescence. In vitro methylation assay, in-cell methylation, protein expression analysis, ROS measurement, p38MAPK activation assay Oncotarget Medium 26992231
2017 NSUN2 is the principal RNA methyltransferase for m5C in mRNAs; m5C is enriched in CG-rich regions downstream of translation initiation sites; the mRNA export adaptor ALYREF specifically recognizes m5C-modified mRNA; NSUN2 modulates ALYREF nuclear-cytoplasmic shuttling and mRNA export; export defects upon NSUN2 depletion are rescued by wild-type but not methyltransferase-defective NSUN2. Transcriptome-wide m5C profiling (bisulfite-seq), in vitro and in vivo binding studies, nuclear-cytoplasmic fractionation, NSUN2 catalytic mutant rescue experiments, RNA export assays Cell research High 28418038
2017 NSUN2 catalyzes m5C modification on p21 3′-UTR; METTL3/METTL14 catalyzes m6A on the same mRNA; m6A methylation by METTL3/METTL14 facilitates NSUN2-mediated m5C, and vice versa; combined m5C and m6A synergistically enhance p21 translation during oxidative stress-induced senescence. In vitro methylation assay, translation reporter assay, KD of NSUN2 and METTL3/METTL14, LC-MS/MS Journal of cellular biochemistry Medium 28247949
2017 NSun2 methylates IL-17A mRNA at cytosine C466 in vitro and in vivo; this m5C methylation promotes IL-17A translation in T lymphocytes; homocysteine upregulates NSun2, driving IL-17A upregulation; NSun2-/- rats show markedly decreased plasma IL-17A. In vitro methylation assay, bisulfite sequencing, HPLC-MS, luciferase reporter assay, NSun2-/- rats Biochemical and biophysical research communications Medium 28919411
2019 NSUN2 is imported into the matrix of mammalian mitochondria and introduces m5C at positions 48, 49, and 50 of several mitochondrial tRNAs; three genetic models (KO mice, patient fibroblasts, CRISPR KO in human cells) confirm NSUN2 dependence; NSUN2 inactivation does not profoundly affect mt-tRNA stability or oxidative phosphorylation in differentiated cells. Spatially restricted proximity labeling (BioID), immunodetection, KO mice, patient fibroblasts, CRISPR/Cas9 KO, mass spectrometric tRNA modification mapping Nucleic acids research High 31276587
2019 NSUN2 introduces m5C at positions 48–50 of eight mouse and six human mitochondrial tRNAs, confirmed by mass spectrometry; NSUN2 foci inside mitochondria were visualized by structured illumination microscopy; in vitro reconstitution of m5C at mt-tRNA positions 48–50 was achieved with purified NSUN2 and SAM. Mass spectrometry of modified tRNA nucleosides, Nsun2 KO mice, CRISPR/Cas9 KO human cells, in vitro methylation reconstitution, structured illumination microscopy Nucleic acids research High 31287866
2020 NSun2 methylates the 3′-UTR of autotaxin (ATX) mRNA at cytosine C2756 in vitro and in vivo, enhancing ATX mRNA translation; NSun2-mediated m5C also promotes nuclear-to-cytoplasmic export of ATX mRNA in an ALYREF-dependent manner; NSun2 knockdown suppresses cell migration, rescued by exogenous LPA. In vitro methylation assay, in-cell bisulfite sequencing, protein expression analysis, mRNA export assay, ALYREF siRNA rescue, cell migration assay The Journal of biological chemistry High 33093178
2021 Neuronal Nsun2 deficiency decreases tRNA m5C levels, causing deficits in expression of tRNAGly isodecoders, glycine codon-specific translational efficiency defects, and loss of Gly-rich synaptic proteins; this impairs glutamatergic neurotransmission and contextual fear memory, and increases glycine biosynthesis. Conditional Nsun2 KO and OE in mouse prefrontal cortex, bisulfite-seq of tRNAs, quantitative proteomics, ribosome profiling Nature communications High 34389722
2021 NSUN2 induces m5C modification of GRB2 mRNA; the m5C reader LIN28B binds m5C-modified GRB2 mRNA and stabilizes it; elevated GRB2 activates PI3K/AKT and ERK/MAPK signaling to promote esophageal cancer progression; E2F1 transcriptionally regulates NSUN2 expression. RNA-bisulfite sequencing, RIP, mRNA stability assay, KO mouse models, functional cancer assays Oncogene Medium 34345012
2021 SUMO-2/3 directly interacts with NSUN2, stabilizing it and mediating its nuclear transport, thereby facilitating NSUN2's oncogenic m5C methyltransferase activity in gastric cancer cells. Co-immunoprecipitation, nuclear transport assay, m5C bisulfite sequencing, gain/loss-of-function assays Cell death & disease Medium 34504059
2022 NSUN2 promotes m5C methylation of KRT13 mRNA; the m5C reader YBX1 recognizes and stabilizes methylated KRT13 mRNA; only wild-type NSUN2 (not catalytically inactive mutant) rescues migration and invasion in cervical cancer cells, establishing catalytic activity dependence for oncogenic function. RNA-bisulfite sequencing, RIP-qPCR, catalytic-dead NSUN2 mutant rescue experiment, cell migration/invasion assay Frontiers in oncology Medium 35280737
2022 NSun2 deficiency in mouse CD4+ T cells specifically inhibits Th17 cell differentiation and alleviates colitis; RORγt recruits Nsun2 to chromatin at Il17a and Il17f loci, leading to transcription-coupled m5C formation on nascent mRNAs and enhanced mRNA stability. Conditional T-cell Nsun2 KO mice, colitis model, ChIP, mRNA stability assay, RIP Nature communications High 36792629
2022 NSun2 deficiency promotes tau hyperphosphorylation; conditional brain-specific ablation of NSun2 decreases miR-125b m6A levels; Drosophila NSun2 reduction exacerbates tau toxicity while overexpression partially rescues it; NSun2 levels decrease in response to amyloid-beta oligomers, and NSun2 overexpression rescues AβO-induced tau phosphorylation. Conditional brain-specific KO mice, Drosophila tau toxicity model, iPSC-derived neurons, Western blot, immunostaining, miRNA modification analysis Acta neuropathologica Medium 36357715
2023 NSUN2 methylates QSOX1 mRNA coding sequence; the m5C reader YBX1 recognizes methylated QSOX1 and enhances its translation, conferring gefitinib resistance in EGFR-mutant NSCLC; this defines the NSUN2-YBX1-QSOX1 axis. RNA-BisSeq, m5C-BisSeq, RNA-seq, MeRIP-qPCR, puromycin incorporation translation assay, gain/loss-of-function, in vivo xenograft Molecular cancer Medium 37161388
2023 Glucose directly binds to NSUN2 at amino acids 1-28, promoting NSUN2 oligomerization and activation; activated NSUN2 maintains global m5C RNA methylation including TREX2 mRNA, stabilizing TREX2 to restrict cytosolic dsDNA and suppress cGAS/STING activation; NSUN2 mutants defective in glucose binding abolish this activity. Glucose-binding assay, oligomerization assay, NSUN2 glucose-binding mutant, TREX2 mRNA stability, cGAS/STING pathway assays, in vivo tumor models Cell metabolism High 37586363
2023 NSUN2 methylates IRF3 mRNA and accelerates its degradation, reducing IRF3 levels and IFN-β production; knockout of NSUN2 enhances type I interferon responses during viral infections including SARS-CoV-2; viral infection reduces endogenous NSUN2 levels to boost antiviral responses. NSUN2 KO cells and mice, bisulfite sequencing of IRF3 mRNA, mRNA stability assay, IRF3 m5C site mutation, viral infection models Emerging microbes & infections Medium 36748584
2023 NSUN2-mediated m5C modification of HBV RNA at sites C2017 and C131 promotes HBV RNA stability and replication; mutation of these m5C sites decreases HBV expression; HBV core protein promotes NSUN2 expression, establishing a positive feedback loop. Bisulfite sequencing of HBV RNA, high-throughput bisulfite-seq, site-directed mutagenesis of HBV m5C sites, NSUN2 KD/KO, HBV replication assay, Nsun2+/- mice PLoS pathogens Medium 38048324
2023 NSUN2 mediates m5C modification of SLC7A11 mRNA; the m5C reader YBX1 recognizes m5C sites on SLC7A11 mRNA via its cold shock domain, increasing SLC7A11 mRNA stability and protein levels, thereby conferring ferroptosis resistance in endometrial cancer. RNA bisulfite sequencing, RIP-qPCR (YBX1), mRNA stability assay, YBX1 domain mapping, NSUN2 KD/rescue, ferroptosis assay Redox biology Medium 38042059
2023 Cysteine-directed covalent inhibitors (azetidine acrylamides) stereoselectively target the conserved catalytic cysteine of NSUN2, inhibiting its methyltransferase activity on recombinant NSUN2 but not NSUN6 in vitro, and disrupting NSUN2-tRNA interactions in cancer cells, globally reducing tRNA m5C content. Activity-based protein profiling (ABPP), recombinant NSUN2 in vitro activity assay, cell-based tRNA m5C quantification, proteome-wide selectivity profiling Angewandte Chemie (International ed. in English) High 37909922
2023 DIAPH2-AS1 lncRNA binds NSUN2 and protects it from ubiquitin-proteasomal degradation by masking lysines K577 and K579; stabilized NSUN2 increases m5C modification of NTN1 mRNA, enhancing its stability and promoting neural invasion of gastric cancer. Pulldown assay, RIP assay, ubiquitination assay, K577/K579 mutation, mRNA stability assay, in vivo neural invasion model Cell death & disease Medium 37037818
2024 Glucose binds conserved sequences within NSUN2, enhancing its binding to S-adenosyl-L-methionine and boosting its enzymatic activity; glucose enhances NSUN2's proximity to mRNA translation machinery; NSUN2 modulates global mRNA translation, particularly of pro-differentiation mRNAs with m5C modifications such as GRHL3, facilitating epidermal differentiation. Glucose-binding assay, SAM-binding assay, enzymatic activity assay, proximity labeling, ribosome profiling/translation assay, epidermal differentiation model Nucleic acids research High 39565212
2024 STUB1 ubiquitinates NSUN2 at lysines K457 and K654, promoting NSUN2 degradation during ferroptosis; loss of NSUN2 reduces m5C methylation of Gpx4 mRNA 3′-UTR, abrogating the interaction between SBP2 and the SECIS element, thereby inhibiting GPX4 protein synthesis and promoting hepatocyte ferroptosis. Co-IP for STUB1-NSUN2 interaction, ubiquitination site mapping (K457/K654 mutants), MeRIP for Gpx4 m5C, SBP2-SECIS interaction assay, NSUN2 restoration rescue assay Cell reports High 39453812
2024 NAA10 (N-α-acetyltransferase 10) lactylates NSUN2 at lysine K508, enhancing NSUN2 enzymatic activity; activated NSUN2 methylates GCLC mRNA, stabilizing it and increasing intracellular glutathione, conferring ferroptosis resistance; K508R NSUN2 mutant or GCLC m5C site mutants abolish these effects. Lactylation site mapping (K508), NSUN2 K508R mutant, Co-IP (NSUN2-NAA10 interaction), m5C methylation of GCLC mRNA, mRNA stability assay, GSH measurement, ferroptosis assay Redox biology High 39742570
2024 NSUN2 and YBX1 mediate m5C modification of ENO1 mRNA; ENO1 m5C modification reprograms glucose metabolism increasing lactic acid; lactic acid activates NSUN2 transcription via histone H3K18 lactylation and induces NSUN2 lactylation at K356 critical for target RNA capture, forming a positive feedback loop. m5C-RIP-seq, RIP-qPCR, metabolic assays, ChIP for H3K18la, lactylation site identification (K356), K356 mutant functional assay Advanced science Medium 38769664
2024 Nsun2 methylates PRKACA (PKA catalytic subunit alpha) mRNA; the m5C reader YBX1 recognizes methylated PRKACA mRNA and promotes its translation; Nsun2 ablation reduces PKA activity, impairs cardiomyocyte contraction and calcium handling, and blocks hypertrophic response in mice. m5C-RIP-seq, RNA pull-down, polysome profiling, reporter assay, cardiac-specific Nsun2 KO (αMHC-CreERT2), rAAV9-mediated OE, IonOptix calcium transient measurement Theranostics High 39990213
2025 NSUN2 catalyzes m5C deposition on the 3′-UTR of FSP1 (ferroptosis suppressor protein 1) mRNA; the m5C reader YBX1 recognizes and stabilizes FSP1 mRNA, protecting AML cells from ferroptosis; catalytically inactive NSUN2 (C271A/C321A) or non-functional FSP1 mutants fail to rescue ferroptosis resistance. m5C-RIP-seq, RIP-qPCR, mRNA stability assay, NSUN2 catalytic dead mutant (C271A/C321A), FSP1 functional mutants, xenograft models, pharmacological NSUN2 inhibition (MY-1B) Molecular cancer Medium 40691844
2025 NSUN2 acts as a writer and ALYREF as a reader of m5C on SRSF6 mRNA, inducing alternative splicing reprogramming that switches UAP1 isoform from AGX1 to AGX2; AGX2 enhances N-linked glycosylation of ABC transporters, preventing their ubiquitination-mediated degradation and conferring multidrug resistance in anaplastic thyroid cancer. MeRIP-seq, transcriptomic/proteomic analysis, alternative splicing analysis, glycoprotein staining, denaturing IP ubiquitination assay, nuclear-cytoplasmic fractionation, NSUN2 inhibitor, spontaneous ATC mouse KO model Theranostics Medium 40083919
2025 NSUN2 mediates m5C modification of tRNAVal-CAC, enhancing codon-frequency-dependent translation of glycolysis-related genes (ALDH3A2, ALDH7A1, HK1, PFKM); depletion of NSUN2 disrupts tRNAVal-CAC m5C, impairs translation of these enzymes, and suppresses glycolysis and TNBC progression. tRNA m5C bisulfite sequencing, ribosome sequencing (Ribo-seq), codon usage bias analysis, glycolysis assays, KD/OE functional studies, xenograft models Cellular & molecular biology letters Medium 40855521

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m5C reader. Cell research 878 28418038
2012 RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nature structural & molecular biology 493 22885326
2013 NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs. Cell reports 467 23871666
2017 NSUN2-Mediated m5C Methylation and METTL3/METTL14-Mediated m6A Methylation Cooperatively Enhance p21 Translation. Journal of cellular biochemistry 239 28247949
2006 The RNA methyltransferase Misu (NSun2) mediates Myc-induced proliferation and is upregulated in tumors. Current biology : CB 231 16713953
2012 Mutations in NSUN2 cause autosomal-recessive intellectual disability. American journal of human genetics 224 22541559
2020 Aberrant NSUN2-mediated m5C modification of H19 lncRNA is associated with poor differentiation of hepatocellular carcinoma. Oncogene 223 32978516
2021 NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation. Cell death & disease 196 34504059
2020 The RNA Methyltransferase NSUN2 and Its Potential Roles in Cancer. Cells 196 32708015
2012 Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability. American journal of human genetics 193 22541562
2023 Aberrant m5C hypermethylation mediates intrinsic resistance to gefitinib through NSUN2/YBX1/QSOX1 axis in EGFR-mutant non-small-cell lung cancer. Molecular cancer 185 37161388
2023 NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. Cell metabolism 177 37586363
2011 The RNA-methyltransferase Misu (NSun2) poises epidermal stem cells to differentiate. PLoS genetics 173 22144916
1999 Multisite-specific tRNA:m5C-methyltransferase (Trm4) in yeast Saccharomyces cerevisiae: identification of the gene and substrate specificity of the enzyme. RNA (New York, N.Y.) 168 10445884
2021 NSUN2-mediated RNA 5-methylcytosine promotes esophageal squamous cell carcinoma progression via LIN28B-dependent GRB2 mRNA stabilization. Oncogene 164 34345012
2024 Metabolic Recoding of NSUN2-Mediated m5C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m5C-ENO1 Positive Feedback Loop. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 150 38769664
2019 NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs. Nucleic acids research 137 31276587
2020 RNA methyltransferase NSUN2 promotes gastric cancer cell proliferation by repressing p57Kip2 by an m5C-dependent manner. Cell death & disease 136 32332707
2013 The mouse cytosine-5 RNA methyltransferase NSun2 is a component of the chromatoid body and required for testis differentiation. Molecular and cellular biology 134 23401851
2012 The tRNA methyltransferase NSun2 stabilizes p16INK⁴ mRNA by methylating the 3'-untranslated region of p16. Nature communications 134 22395603
2009 The nucleolar RNA methyltransferase Misu (NSun2) is required for mitotic spindle stability. The Journal of cell biology 133 19596847
2018 Novel long noncoding RNA NMR promotes tumor progression via NSUN2 and BPTF in esophageal squamous cell carcinoma. Cancer letters 119 29763634
2023 Epigenetically upregulated NSUN2 confers ferroptosis resistance in endometrial cancer via m5C modification of SLC7A11 mRNA. Redox biology 103 38042059
2015 NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation. Aging 103 26687548
2016 NSun2 Deficiency Protects Endothelium From Inflammation via mRNA Methylation of ICAM-1. Circulation research 95 26838785
2019 Mammalian NSUN2 introduces 5-methylcytidines into mitochondrial tRNAs. Nucleic acids research 94 31287866
2015 NSun2 Promotes Cell Growth via Elevating Cyclin-Dependent Kinase 1 Translation. Molecular and cellular biology 94 26391950
2017 Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer. Oncotarget 89 27447970
2014 Methylation by NSun2 represses the levels and function of microRNA 125b. Molecular and cellular biology 89 25047833
2017 Cytosolic YB-1 and NSUN2 are the only proteins recognizing specific motifs present in mRNAs enriched in exosomes. Biochimica et biophysica acta. Proteins and proteomics 87 28341602
2023 m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization. Cell death & disease 84 36806253
2023 NSUN2 promotes osteosarcoma progression by enhancing the stability of FABP5 mRNA via m5C methylation. Cell death & disease 77 36792587
2007 Aurora-B regulates RNA methyltransferase NSUN2. Molecular biology of the cell 75 17215513
2021 Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior. Nature communications 71 34389722
2009 Genomic gain of 5p15 leads to over-expression of Misu (NSUN2) in breast cancer. Cancer letters 71 19740597
2017 Homocysteine upregulates interleukin-17A expression via NSun2-mediated RNA methylation in T lymphocytes. Biochemical and biophysical research communications 66 28919411
2024 NSUN2 promotes colorectal cancer progression by enhancing SKIL mRNA stabilization. Clinical and translational medicine 62 38468490
2020 NSun2 promotes cell migration through methylating autotaxin mRNA. The Journal of biological chemistry 62 33093178
2023 Peritoneal high-fat environment promotes peritoneal metastasis of gastric cancer cells through activation of NSUN2-mediated ORAI2 m5C modification. Oncogene 61 37130916
2024 NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis. Redox biology 60 39742570
2023 NSUN2-mediated m5 C RNA methylation dictates retinoblastoma progression through promoting PFAS mRNA stability and expression. Clinical and translational medicine 60 37228185
2022 Distinct Roles of m5C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers. Frontiers in oncology 58 35280737
2012 The human tRNA m (5) C methyltransferase Misu is multisite-specific. RNA biology 55 22995836
2023 Chemical Proteomic Discovery of Isotype-Selective Covalent Inhibitors of the RNA Methyltransferase NSUN2. Angewandte Chemie (International ed. in English) 54 37909922
2023 The m5 C methyltransferase NSUN2 promotes codon-dependent oncogenic translation by stabilising tRNA in anaplastic thyroid cancer. Clinical and translational medicine 52 37983928
2022 RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer. Oncogene 52 35501460
2022 NSUN2-mediated mRNA m5C Modification Regulates the Progression of Hepatocellular Carcinoma. Genomics, proteomics & bioinformatics 52 36183976
2022 Positive epigenetic regulation loop between AR and NSUN2 promotes prostate cancer progression. Clinical and translational medicine 51 36169095
2024 NSUN2/YBX1 promotes the progression of breast cancer by enhancing HGH1 mRNA stability through m5C methylation. Breast cancer research : BCR 49 38844963
2023 NSUN2 stimulates tumor progression via enhancing TIAM2 mRNA stability in pancreatic cancer. Cell death discovery 48 37393317
2023 NSUN2-mediated M5c methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections. Emerging microbes & infections 47 36748584
2023 Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis. Nature communications 47 36792629
2023 Long noncoding RNA DIAPH2-AS1 promotes neural invasion of gastric cancer via stabilizing NSUN2 to enhance the m5C modification of NTN1. Cell death & disease 46 37037818
2023 NSUN2-mediated m5C modification of HBV RNA positively regulates HBV replication. PLoS pathogens 45 38048324
2016 RNA methyltransferase NSUN2 promotes stress-induced HUVEC senescence. Oncotarget 42 26992231
2015 A Novel Single-Nucleotide Deletion (c.1020delA) in NSUN2 Causes Intellectual Disability in an Emirati Child. Journal of molecular neuroscience : MN 42 26055038
2024 5-Methylcytosine transferase NSUN2 drives NRF2-mediated ferroptosis resistance in non-small cell lung cancer. The Journal of biological chemistry 41 38403250
2021 FOXC2-AS1 stabilizes FOXC2 mRNA via association with NSUN2 in gastric cancer cells. Human cell 38 34324140
2017 Association of tRNA methyltransferase NSUN2/IGF-II molecular signature with ovarian cancer survival. Future oncology (London, England) 38 28829218
2016 mRNA methylation by NSUN2 in cell proliferation. Wiley interdisciplinary reviews. RNA 36 27444144
2022 RNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation. Acta neuropathologica 32 36357715
2024 NSUN2 regulates Wnt signaling pathway depending on the m5C RNA modification to promote the progression of hepatocellular carcinoma. Oncogene 31 39375506
2021 RNA methyltransferase NSUN2 promotes hypopharyngeal squamous cell carcinoma proliferation and migration by enhancing TEAD1 expression in an m5C-dependent manner. Experimental cell research 31 34048786
2022 NSUN2-mediated RNA m5C modification modulates uveal melanoma cell proliferation and migration. Epigenetics 30 35757999
2019 Transfer RNA methyltransferase gene NSUN2 mRNA expression modifies the effect of T cell activation score on patient survival in head and neck squamous carcinoma. Oral oncology 29 31887619
2025 The RNA M5C methyltransferase NSUN2 promotes progression of hepatocellular carcinoma by enhancing PKM2-mediated glycolysis. Cell death & disease 28 39924557
2025 NSUN2-mediated m5C modification drives alternative splicing reprogramming and promotes multidrug resistance in anaplastic thyroid cancer through the NSUN2/SRSF6/UAP1 signaling axis. Theranostics 28 40083919
2023 NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress. Cell death discovery 28 36739432
2022 5-methylcytosine modification by Plasmodium NSUN2 stabilizes mRNA and mediates the development of gametocytes. Proceedings of the National Academy of Sciences of the United States of America 27 35210361
2020 NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell recruitment. Cellular and molecular life sciences : CMLS 27 32734582
2022 NSUN2 gene rs13181449 C>T polymorphism reduces neuroblastoma risk. Gene 23 36529349
2014 Trm4 and Nsun2 RNA:m5C methyltransferases form metabolite-dependent, covalent adducts with previously methylated RNA. Biochemistry 23 25375641
2024 NSUN2 promotes lung adenocarcinoma progression through stabilizing PIK3R2 mRNA in an m5C-dependent manner. Molecular carcinogenesis 22 38411298
2024 RNA methyltransferase NSUN2-mediated m5C methylation promotes Cr(VI)-induced malignant transformation and lung cancer by accelerating metabolism reprogramming. Environment international 22 39395236
2024 NSUN2-mediated RNA methylation: Molecular mechanisms and clinical relevance in cancer. Cellular signalling 21 39218271
2024 Aberrant NSUN2-mediated m5C modification of exosomal LncRNA MALAT1 induced RANKL-mediated bone destruction in multiple myeloma. Communications biology 21 39358426
2024 LINC00618 facilitates growth and metastasis of hepatocellular carcinoma via elevating cholesterol synthesis by promoting NSUN2-mediated SREBP2 m5C modification. Ecotoxicology and environmental safety 20 39299205
2023 Suppression of NSUN2 enhances the sensitivity to chemosensitivity and inhibits proliferation by mediating cell apoptosis in gastric cancer. Pathology, research and practice 19 38039743
2022 ROR2 Downregulation Activates the MSX2/NSUN2/p21 Regulatory Axis and Promotes Dental Pulp Stem Cell Senescence. Stem cells (Dayton, Ohio) 18 35356984
2025 NSUN2-mediated cytosine-5 methylation of FSP1 protects acute myeloid leukemia cells from ferroptosis. Molecular cancer 17 40691844
2023 The RNA m5C Methylase NSUN2 Modulates Corneal Epithelial Wound Healing. Investigative ophthalmology & visual science 17 36862118
2019 Division of labour: tRNA methylation by the NSun2 tRNA methyltransferases Trm4a and Trm4b in fission yeast. RNA biology 17 30646830
2021 RNA methyltransferase NSUN2 promotes growth of hepatocellular carcinoma cells by regulating fizzy-related-1 in vitro and in vivo. The Kaohsiung journal of medical sciences 16 34370374
2003 Novel gamma-1 herpesviruses identified in free-ranging new world monkeys (golden-handed tamarin [Saguinus midas], squirrel monkey [Saimiri sciureus], and white-faced saki [Pithecia pithecia]) in French Guiana. Journal of virology 16 12885928
2025 Novel molecular mechanisms of immune evasion in hepatocellular carcinoma: NSUN2-mediated increase of SOAT2 RNA methylation. Cancer communications (London, England) 15 40227950
2024 NSUN2-Mediated m5C Methylation Impairs Endometrial Receptivity. Laboratory investigation; a journal of technical methods and pathology 15 38237738
2024 STUB1-mediated ubiquitination and degradation of NSUN2 promotes hepatocyte ferroptosis by decreasing m5C methylation of Gpx4 mRNA. Cell reports 15 39453812
2024 NSUN2-mediated R-loop stabilization as a key driver of bladder cancer progression and cisplatin sensitivity. Cancer letters 15 39732321
2010 Crystal structure of Methanocaldococcus jannaschii Trm4 complexed with sinefungin. Journal of molecular biology 15 20600111
2025 NSUN2-tRNAVal-CAC-axis-regulated codon-biased translation drives triple-negative breast cancer glycolysis and progression. Cellular & molecular biology letters 14 40855521
2024 NSUN2 relies on ALYREF to regulate Nrf2-mediated oxidative stress and alleviate Dox-induced liver injury. Biology direct 14 38685056
2025 NSUN2/ALYREF axis-driven m5C methylation enhances PD-L1 expression and facilitates immune evasion in non-small-cell lung cancer. Cancer immunology, immunotherapy : CII 13 40029463
2023 Overview of distinct 5-methylcytosine profiles of messenger RNA in normal and knock-down NSUN2 colorectal cancer cells. Frontiers in genetics 13 37168511
2025 Diffuse large B-cell lymphoma cell-derived exosomal NSUN2 stabilizes PDL1 to promote tumor immune escape and M2 macrophage polarization in a YBX1-dependent manner. Archives of biochemistry and biophysics 12 39864779
2025 Nsun2 controls cardiac homeostasis and hypertrophic response by regulating PRKACA expression. Theranostics 12 39990213
2024 NSUN2 mediates distinct pathways to regulate enterovirus 71 replication. Virologica Sinica 12 38768712
2025 NSUN2-mediated m5C modification of circFAM190B promotes lung cancer progression by inhibiting cellular autophagy. International journal of biological macromolecules 11 40020806
2024 NSUN2 affects diabetic retinopathy progression by regulating MUC1 expression through RNA m5C methylation. Journal of translational medicine 11 38764010
2024 Fat mass and obesity-associated protein inhibit the pathology of rheumatoid arthritis through the NSUN2/SFRP1/Wnt/β-catenin signal axis. The Journal of pharmacy and pharmacology 10 38243394
2024 Glucose binds and activates NSUN2 to promote translation and epidermal differentiation. Nucleic acids research 9 39565212

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