Affinage

FTSJ1

tRNA (cytidine(32)/guanosine(34)-2'-O)-methyltransferase · UniProt Q9UET6

Length
329 aa
Mass
36.1 kDa
Annotated
2026-06-09
23 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FTSJ1 is a conserved eukaryotic tRNA 2'-O-methyltransferase that modifies the anticodon loop of multiple cytosolic tRNAs and is required for accurate, efficient translation, with loss of function causing nonsyndromic X-linked intellectual disability (PMID:15162322, PMID:33771871). Catalysis is performed by a Rossmann-fold methyltransferase domain that partners with distinct auxiliary subunits to direct position specificity: FTSJ1 binds WDR6 to methylate position 34 (Gm34) and THADA to methylate position 32 (Cm32/Nm32), in each case docking the partner through its C-terminal region via structurally distinct interaction modes (PMID:31586407, PMID:32558197, PMID:40483304). These anticodon-loop modifications are hierarchically interdependent, with Cm32 and m1G37 acting as prerequisites for Gm34 (PMID:31586407, PMID:32558197). Functionally, loss of FTSJ1 selectively impairs decoding of Phe codons—reducing UUU codon translation efficiency and lowering steady-state brain tRNA-Phe—which reduces translation of synaptic genes and produces immature synaptic morphology, aberrant plasticity, behavioral and memory deficits, and aberrant neurite/spine morphology in neural progenitor–derived neurons (PMID:32558197, PMID:33771871, PMID:36720500). Beyond its neuronal role, FTSJ1 modulates cancer cell phenotypes through effects on target gene expression including DRAM1, PGK1-driven glycolysis, and IL1RN mRNA stability (PMID:32393790, PMID:39695074, PMID:41816574); the precise molecular basis linking tRNA methylation to these downstream targets is not resolved in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2004 Medium

    Establishing that an RNA methyltransferase gene underlies a Mendelian cognitive disorder linked translation regulation to brain function, defining FTSJ1's clinical and molecular identity.

    Evidence Mutation screening and expression studies across multiple XLID families, including a splice mutation causing exon skipping

    PMID:15162322 PMID:15342698

    Open questions at the time
    • No enzymatic substrate identified at this stage
    • Mechanism connecting methyltransferase loss to cognition unknown
  2. 2008 Medium

    Demonstrating that a pathogenic FTSJ1 splice mutation is cleared by nonsense-mediated decay clarified that loss of function results from transcript elimination rather than production of a toxic truncated protein.

    Evidence qRT-PCR with cycloheximide NMD inhibition in patient lymphoblasts

    PMID:18081026

    Open questions at the time
    • Does not address residual function of any escaping transcript
    • No connection yet to specific tRNA substrate
  3. 2015 High

    Identifying that FTSJ1 generates Cm32 and Gm34 on tRNA-Phe (and indirectly o2yW37) gave the disease gene a concrete biochemical activity and singled out Gm34 as the critical modification via an allele that abolishes only Gm34.

    Evidence Mass spectrometry of patient cell tRNAs plus parallel yeast trm7 mutant analysis and binding assays

    PMID:26310293

    Open questions at the time
    • Direct enzymatic reconstitution not yet performed in human system
    • Auxiliary subunit identity for each position unresolved
  4. 2019 High

    Crystal structures of the yeast Trm7-Trm734 complex with reconstituted activity defined the catalytic Rossmann fold, the WD40 docking partner, and the substrate prerequisites (Cm32/m1G37/pyrimidine-34) for position-34 methylation.

    Evidence Crystallography (apo and SAM-bound), SAXS, in vitro methylation with tRNA variants, mutagenesis mimicking an XLID allele

    PMID:31586407

    Open questions at the time
    • Structures are of yeast orthologs, not human FTSJ1
    • Position-32 complex not structurally resolved here
  5. 2020 High

    Reconstituting the human FTSJ1-WDR6 complex and showing codon-selective translation defects established the in vivo enzyme assembly, the hierarchical modification order, and a direct functional consequence (impaired UUU but not UUC decoding).

    Evidence Co-IP, in vitro reconstitution, MS modification mapping, codon-specific translation efficiency in knockout cells

    PMID:32558197

    Open questions at the time
    • Identity of the position-32 partner not addressed here
    • How codon-specific decoding loss propagates to phenotype unresolved
  6. 2020 High

    Drosophila genetics partitioned the two catalytic activities between orthologs (position 34 vs position 32) and revealed roles beyond translation, in small RNA silencing and antiviral defense.

    Evidence Genetic knockout, MALDI-TOF and RiboMethSeq modification mapping, small RNA pathway phenotyping

    PMID:31943105

    Open questions at the time
    • Mechanistic link between anticodon methylation and small RNA pathways unexplained
    • Relevance of antiviral role to mammals untested
  7. 2021 High

    An Ftsj1 knockout mouse connected the molecular defect to physiology by showing selective brain tRNA-Phe depletion, reduced translation of synaptic genes, and corresponding synaptic, plasticity, and behavioral deficits.

    Evidence Knockout mouse with RiboMethSeq, ribosome profiling, electrophysiology, behavior, and morphology, validated in patient cells

    PMID:33771871

    Open questions at the time
    • Why tRNA-Phe is selectively destabilized over other targets unclear
    • Causal chain from translation change to behavior not fully dissected
  8. 2022 Medium

    Mapping a conserved RRSAGLP motif in the DUF2428 domain required for activity in both yeast Trm732 and human THADA identified THADA as the position-32 auxiliary subunit and a functional element it contributes.

    Evidence Site-directed mutagenesis with in vivo yeast complementation and tRNA modification analysis

    PMID:35559166

    Open questions at the time
    • Structural basis of THADA contribution not yet resolved here
    • Direct human reconstitution not shown in this study
  9. 2025 High

    The cryo-EM structure of the human FTSJ1-THADA complex with and without tRNA explained position-32 specificity, showing tRNA anchored within THADA and a C-terminal docking mode distinct from FTSJ1-WDR6.

    Evidence Cryo-EM of human complex with/without substrate plus mutagenesis of THADA tRNA-recognition residues

    PMID:40483304

    Open questions at the time
    • Catalytic transition state not captured
    • Coordination/competition between WDR6 and THADA complexes in cells unaddressed
  10. 2024 Medium

    FTSJ1 was implicated in cancer metabolism and growth, where its loss enhances PGK1-driven glycolysis (and elsewhere DRAM1 and IL1RN regulation), expanding its role beyond neuronal translation.

    Evidence Loss/gain-of-function with metabolic assays, glycolytic inhibitor rescue, and tumor sample correlation; complemented by DRAM1 and IL1RN studies

    PMID:32393790 PMID:39695074 PMID:41816574

    Open questions at the time
    • Direct tRNA-modification-to-target mechanism not established
    • Single-lab findings per tumor type without cross-validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How position-specific anticodon methylation by FTSJ1 mechanistically translates into selective tRNA-Phe destabilization, neuronal phenotypes, and the diverse cancer-associated gene expression changes remains unresolved.
  • No mechanism linking specific Nm modifications to tRNA stability
  • Connection between methyltransferase activity and DRAM1/PGK1/IL1RN regulation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 6 GO:0016740 transferase activity 3 GO:0003723 RNA binding 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-392499 Metabolism of proteins 2
Partners
THADAWDR6
Complex memberships
FTSJ1-THADA complexFTSJ1-WDR6 complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 FTSJ1 encodes a homolog of E. coli RNA methyltransferase FtsJ/RrmJ; loss-of-function mutations (splicing defect, nonsense mutation, frameshift deletion) abolish or significantly reduce FTSJ1 transcript levels and cause nonsyndromic X-linked intellectual disability, establishing FTSJ1 as a functional RNA methyltransferase implicated in translation regulation. Mutation screening, direct sequencing, expression studies (RT-PCR, Western) in patient-derived cell lines American journal of human genetics Medium 15162322
2004 A splice-site mutation in FTSJ1 (IVS3-2A>G) in the MRX9 family causes exon 4 skipping and a premature stop codon in exon 5, leading to a severely truncated protein and X-linked intellectual disability. Direct sequencing, RT-PCR splicing analysis in patient-derived samples Journal of medical genetics Medium 15342698
2008 A donor splice-site mutation in FTSJ1 intron 8 (c.571+1G>A) causes intron retention, frameshift, and premature termination; the mutant mRNA is degraded by nonsense-mediated mRNA decay (NMD), confirmed by cycloheximide rescue of mRNA levels. Sequencing, quantitative RT-PCR, cycloheximide (NMD inhibitor) treatment of patient lymphoblast cells American journal of medical genetics. Part B, Neuropsychiatric genetics Medium 18081026
2015 FTSJ1 (human TRM7 ortholog) is required for 2'-O-methylation at positions C32 (Cm32) and G34 (Gm34) of tRNA-Phe anticodon loop, and indirectly for peroxywybutosine (o2yW) at position 37; patient cell lines with loss-of-function FTSJ1 mutations nearly completely lack Cm32 and Gm34. A missense allele FTSJ1-p.A26P specifically abolishes Gm34 but preserves Cm32 and o2yW, implicating Gm34 as the critical modification. Mass spectrometry-based tRNA modification analysis of patient-derived cell lines; parallel yeast trm7-A26P mutant analysis; binding assays for Trm734 interaction Human mutation High 26310293
2019 The yeast Trm7 (FTSJ1 ortholog)-Trm734 complex catalyzes 2'-O-methylation at position 34 of tRNA-Phe, tRNA-Trp, and tRNA-Leu, requiring Cm32, m1G37, or a pyrimidine at position 34 as prerequisite features; crystal structures reveal Trm7 has a Rossmann-fold catalytic domain and Trm734 has three WD40 β-propeller domains forming a V-shaped cleft that docks to Trm7 via its C-terminal region. A point mutation in Trm7 equivalent to an FTSJ1 XLID patient mutation decreases methylation activity. Crystal structure determination (apo and SAM-bound forms), SAXS, in vitro methylation assays with tRNA transcript variants, mutagenesis Nucleic acids research High 31586407
2020 FTSJ1 forms a complex with WDR6; the FTSJ1-WDR6 complex mediates 2'-O-methylation at position 34 (Gm34) of specific tRNAs in vitro, with m1G37 as a prerequisite modification. Modifications at positions 32, 34, and 37 are interdependent and occur in a hierarchical order in vivo. Loss of FTSJ1 selectively reduces translation efficiency of the UUU codon (decoded by tRNA-Phe(GAA)) but not the UUC codon. Co-immunoprecipitation (FTSJ1-WDR6 interaction), in vitro reconstitution of 2'-O-methylation activity, mass spectrometry modification analysis, codon-specific translation efficiency assay in knockout cells EMBO reports High 32558197
2020 In Drosophila, the FTSJ1 ortholog CG7009 methylates the wobble position 34 in tRNA-Phe, tRNA-Trp, and tRNA-Leu, while the second ortholog CG5220 methylates position C32 in the same tRNAs and additional tRNAs. Loss of these modifications disrupts small RNA silencing pathways (piRNA, siRNA) and increases sensitivity to RNA virus infections. Genetic knockout, MALDI-TOF mass spectrometry, RiboMethSeq modification mapping, phenotypic analysis of small RNA pathways Nucleic acids research High 31943105
2020 FTSJ1 mediates 2'-O-methyladenosine (Am) modification in tRNAs in lung cells; loss of FTSJ1 increases DRAM1 expression, promotes cancer cell proliferation and migration, while FTSJ1 overexpression suppresses NSCLC cell growth in vitro and in vivo and reduces DRAM1 levels. HPLC/MS tRNA modification quantification, loss- and gain-of-function assays, RNA-seq, qRT-PCR, rescue assays, xenograft in vivo model Cell death & disease Medium 32393790
2021 Ftsj1 is responsible for 2'-O-methylation of 11 species of cytosolic tRNAs at the anticodon region in mice; Ftsj1 KO selectively reduces steady-state tRNA-Phe levels in the brain, slowing decoding at Phe codons. Ribosome profiling shows reduced translation efficiency for a subset of genes supporting synaptic organization. Ftsj1 KO mice display immature synaptic morphology, aberrant synaptic plasticity, anxiety-like behavior, and memory deficits. Knockout mouse model, RiboMethSeq tRNA modification mapping in KO mice and patient cells, ribosome profiling, electrophysiology (synaptic plasticity), behavioral tests, morphological analysis Science advances High 33771871
2022 A conserved RRSAGLP motif in the DUF2428 domain of yeast Trm732 (human homolog THADA, the FTSJ1 auxiliary subunit for Nm32) is required for tRNA modification activity by both yeast Trm732 and human THADA, establishing that this motif is essential for Trm7/FTSJ1-complex-mediated 2'-O-methylation at position 32. Site-directed mutagenesis of Trm732, in vivo yeast functional complementation assay, tRNA modification analysis ACS omega Medium 35559166
2023 FTSJ1 depletion in human neural progenitor cells differentiating into neurons causes long and thin spine neurites compared to controls; equivalent morphological defects are observed in Drosophila FTSJ1 ortholog mutants and are associated with long-term memory deficits. RiboMethSeq identified novel tRNA targets of FTSJ1 beyond tRNA-Phe, Trp, and Leu. Transcriptome analysis in patient blood cells showed deregulation of genes associated with intellectual disability, and changes in miRNA populations. RiboMethSeq (comprehensive tRNA methylation mapping), transcriptome analysis in patient-derived cells, differentiation of human neural progenitor cells, morphological analysis, Drosophila behavioral (memory) assays Life science alliance Medium 36720500
2025 Cryo-EM structure of the human FTSJ1-THADA complex with and without tRNA substrate reveals that FTSJ1 binds THADA via its C-terminal region through an interaction mode distinct from the FTSJ1-WDR6 complex. The tRNA substrate is anchored inside THADA, and key THADA residues mediating tRNA recognition were identified and validated by mutagenesis, explaining how FTSJ1-THADA specifically mediates Nm32 modification. Cryo-electron microscopy structure determination, biochemical analyses, mutagenesis of THADA residues Communications biology High 40483304
2024 FTSJ1 silencing in NSCLC cells enhances PGK1 expression and translation, promoting glycolysis (increased lactate, pyruvate, ECAR); glycolytic inhibitor 2-DG reverses the proliferation effect. FTSJ1 upregulation suppresses glycolysis. In human NSCLC tumors, FTSJ1 expression negatively correlates with PGK1 levels. Loss- and gain-of-function assays, metabolic assays (ECAR, lactate/pyruvate), qRT-PCR, glycolytic inhibitor rescue, correlative analysis in patient samples Cell death & disease Medium 39695074
2026 FTSJ1 promotes hepatocellular carcinoma progression by reducing RNA stability of the anti-inflammatory gene IL1RN, leading to enhanced pro-inflammatory signaling (downregulated TNF-α and IL-6 via IL1RN loss). FTSJ1 knockdown inhibited HCC cell proliferation, migration, and tumor growth in vivo. RNA-seq, GSEA, in vitro functional assays (CCK-8, Transwell, apoptosis/cell cycle), xenograft in vivo model, cytokine detection Journal of gastrointestinal oncology Medium 41816574

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1. Human mutation 117 26310293
2004 Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation. American journal of human genetics 115 15162322
2021 Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability. Science advances 60 33771871
2004 A splice site mutation in the methyltransferase gene FTSJ1 in Xp11.23 is associated with non-syndromic mental retardation in a large Belgian family (MRX9). Journal of medical genetics 57 15342698
2020 Intellectual disability-associated gene ftsj1 is responsible for 2'-O-methylation of specific tRNAs. EMBO reports 48 32558197
2008 A loss-of-function mutation in the FTSJ1 gene causes nonsyndromic X-linked mental retardation in a Japanese family. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 42 18081026
2007 Loss of SLC38A5 and FTSJ1 at Xp11.23 in three brothers with non-syndromic mental retardation due to a microdeletion in an unstable genomic region. Human genetics 40 17333282
2020 tRNA 2'-O-methylation by a duo of TRM7/FTSJ1 proteins modulates small RNA silencing in Drosophila. Nucleic acids research 39 31943105
2020 FTSJ1 regulates tRNA 2'-O-methyladenosine modification and suppresses the malignancy of NSCLC via inhibiting DRAM1 expression. Cell death & disease 37 32393790
2019 Structure of tRNA methyltransferase complex of Trm7 and Trm734 reveals a novel binding interface for tRNA recognition. Nucleic acids research 21 31586407
2018 A mouse model for intellectual disability caused by mutations in the X-linked 2'‑O‑methyltransferase Ftsj1 gene. Biochimica et biophysica acta. Molecular basis of disease 19 30557699
1993 Localization of a gene responsible for nonspecific mental retardation (MRX9) to the pericentromeric region of the X chromosome. Genomics 18 8288232
2023 Investigating the Inhibition of FTSJ1, a Tryptophan tRNA-Specific 2'-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR. International journal of molecular sciences 14 37298560
2008 Positive association of the FTSJ1 gene polymorphisms with nonsyndromic X-linked mental retardation in young Chinese male subjects. Journal of human genetics 13 18401546
2008 Genetic variations in FTSJ1 influence cognitive ability in young males in the Chinese Han population. Journal of neurogenetics 12 19012053
2023 The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance. Life science alliance 10 36720500
2022 Identification of a Trm732 Motif Required for 2'-O-methylation of the tRNA Anticodon Loop by Trm7. ACS omega 7 35559166
2024 Triple-Negative Breast Cancer Intrinsic FTSJ1 Favors Tumor Progression and Attenuates CD8+ T Cell Infiltration. Cancers 6 38339348
2022 Overexpression of MRX9 impairs processing of RNAs encoding mitochondrial oxidative phosphorylation factors COB and COX1 in yeast. The Journal of biological chemistry 5 35779633
2024 Downregulation of tRNA methyltransferase FTSJ1 by PM2.5 promotes glycolysis and malignancy of NSCLC via facilitating PGK1 expression and translation. Cell death & disease 3 39695074
2020 Correction: FTSJ1 regulates tRNA 2'-O-methyladenosine modification and suppresses the malignancy of NSCLC via inhibiting DRAM1 expression. Cell death & disease 2 32488007
2025 Structural insights into tRNA recognition of the human FTSJ1-THADA complex. Communications biology 1 40483304
2026 FTSJ1-mediated IL1RN mRNA instability promotes inflammation-driven hepatocellular carcinoma. Journal of gastrointestinal oncology 0 41816574

Missed literature

Know a paper Affinage missed for FTSJ1? Flag it for the maintainers and the community.

No submissions yet.