Affinage

TRMT1L

tRNA (guanine(27)-N(2))-dimethyltransferase · UniProt Q7Z2T5

Length
733 aa
Mass
81.7 kDa
Annotated
2026-06-10
10 papers in source corpus 5 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRMT1L is a tRNA methyltransferase that shapes the cytosolic tRNA modification landscape and, through it, global translation and stress resilience (PMID:39786990, PMID:39786998, PMID:39416027). It catalyzes N2,N2-dimethylguanosine (m2,2G): at position 26 of a subset of tRNA-Ala(AGC) isodecoders (PMID:33499731) and, distinct from the related TRMT1 activity, at position 27 of tyrosine tRNAs (PMID:39786990, PMID:39786998). Beyond direct methylation, TRMT1L is required for deposition of acp3U and dihyduridine on select tRNAs (tRNA-Tyr-GUA, tRNA-Cys-GCA, tRNA-Ala-CGC) through a circuit that can be uncoupled from its methyltransferase activity, placing it within a broader tRNA-modification network (PMID:39786990, PMID:39786998, PMID:39416027). Loss of TRMT1L reduces tRNA-Tyr-GUA levels, lowers global mRNA translation rates, and renders cells hypersensitive to oxidative stress (PMID:39786998, PMID:39416027). Consistent with a role in ribosome and tRNA biology, TRMT1L interacts with a component of the Rix1 ribosome biogenesis complex and binds 28S rRNA and a subset of tRNAs (PMID:39786998, PMID:39416027). In neurons, TRMT1L relocalizes from nucleoli to nuclear puncta specifically upon neuronal activation but not heat shock (PMID:33499731), and disruption of its mouse ortholog produces altered motor coordination and exploratory behavior with expression in neural tissues (PMID:17198746), linking the enzyme to neuronal function.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2006 Medium

    Before any molecular activity was known, loss-of-function in the mouse ortholog established that TRMT1L has a physiological role in the nervous system, framing it as a brain-relevant gene.

    Evidence Gene-trap mouse model with behavioral testing and LacZ expression mapping

    PMID:17198746

    Open questions at the time
    • No molecular mechanism connecting the behavioral phenotype to a biochemical activity
    • Single lab
    • Gene-trap may not be a complete null
  2. 2021 High

    The first enzymatic assignment showed TRMT1L is an active m2,2G methyltransferase, resolving its long-unknown biochemical function.

    Evidence NGS, LC-MS/MS, patient-derived and knockout mouse cell lines identifying m2,2G at position 26 of tRNA-Ala(AGC) isodecoders

    PMID:33499731

    Open questions at the time
    • Did not yet define the full substrate repertoire (tRNA-Tyr position 27 came later)
    • Functional consequence for translation not established in this work
  3. 2021 Medium

    Subcellular imaging linked the enzyme to neuronal plasticity by showing stimulus-specific relocalization, distinguishing it from a generic stress response.

    Evidence In vitro neuronal activation model with fluorescence microscopy and heat-shock control

    PMID:33499731

    Open questions at the time
    • Identity and function of the nuclear puncta unknown
    • Mechanism coupling activation to relocalization not defined
    • Single lab
  4. 2025 High

    Independent studies defined tRNA-Tyr position 27 as the principal m2,2G target and revealed a methyltransferase-uncoupled role in acp3U/dihydrouridine deposition, expanding TRMT1L from a single-mark enzyme to a node in a tRNA modification circuit.

    Evidence tRNA-seq, nanopore tRNA-seq, eCLIP-seq and LC-MS/MS in knockout/depletion cell lines, replicated across labs

    PMID:39416027 PMID:39786990 PMID:39786998

    Open questions at the time
    • Mechanism by which TRMT1L promotes acp3U/dihydrouridine independent of catalysis is unknown
    • Enzymes it cooperates with for those marks not identified
  5. 2025 High

    Phenotypic analysis tied the molecular activity to organism-level consequences: TRMT1L loss destabilizes tRNA-Tyr, depresses global translation, and sensitizes cells to oxidative stress.

    Evidence Knockout cell lines with global translation rate assays and oxidative stress viability assays

    PMID:39416027 PMID:39786998

    Open questions at the time
    • Causal chain from m2,2G27 loss to oxidative stress sensitivity not mechanistically dissected
    • Codon-specific translational effects not mapped
  6. 2025 Medium

    Binding studies positioned TRMT1L within ribosome biogenesis machinery, suggesting its tRNA role intersects with rRNA/ribosome processing.

    Evidence eCLIP-seq showing interaction with a Rix1 complex component and binding to 28S rRNA and tRNAs

    PMID:39416027 PMID:39786998

    Open questions at the time
    • No reciprocal validation of the Rix1 component interaction
    • Functional consequence of 28S rRNA binding unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRMT1L mechanistically promotes acp3U and dihydrouridine without catalyzing them, and how its activation-dependent nuclear relocalization connects to translational control in neurons, remain unresolved.
  • Non-catalytic mechanism for acp3U/DHU support undefined
  • Molecular link between neuronal relocalization and tRNA modification not established
  • No structural model of substrate recognition

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-392499 Metabolism of proteins 1

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 TRMT1L is responsible for methylating a subset of cytosolic tRNAAla(AGC) isodecoders at position 26, producing the N2,N2-dimethylguanosine (m2,2G) modification; prior to this work, TRMT1L's enzymatic activity was unknown. Next-generation sequencing, LC-MS/MS, patient-derived cell lines, and knockout mouse models RNA biology High 33499731
2021 Upon neuronal activation (mimicking long-term potentiation) in vitro, TRMT1L undergoes subcellular relocalization from nucleoli to small punctate compartments in the nucleus; this relocalization does not occur upon heat shock, indicating it is specific to neuronal activation rather than a general stress response. Cellular in vitro neuronal activation model, subcellular localization imaging (fluorescence microscopy), heat-shock control experiments RNA biology Medium 33499731
2025 TRMT1L is the enzyme catalyzing m2,2G at position 27 of tyrosine tRNAs (tRNA-Tyr), a modification distinct from TRMT1's activity at position 26; additionally, TRMT1L is required for maintaining 3-(3-amino-3-carboxypropyl)uridine (acp3U) modifications in a subset of tRNAs through a process that can be uncoupled from its methyltransferase activity. Comprehensive tRNA sequencing (tRNA-seq), LC-MS/MS, TRMT1L knockout cell lines Cell reports High 39786990 39786998
2025 TRMT1L depletion impairs deposition of acp3U and dihydrouridine on tRNA-Tyr-GUA, tRNA-Cys-GCA, and tRNA-Ala-CGC, indicating TRMT1L participates in a tRNA modification circuit beyond its direct methyltransferase activity. eCLIP-seq, nanopore tRNA-seq, TRMT1L knockout/depletion cell lines Cell reports High 39416027 39786990 39786998
2025 TRMT1L knockout cells exhibit decreased tRNA-Tyr-GUA levels, reduced global mRNA translation rates, and hypersensitivity to oxidative stress, establishing a functional link between TRMT1L-catalyzed m2,2G27 and translational regulation and cell survival under stress. TRMT1L knockout cell lines, global translation rate assays, oxidative stress viability assays Cell reports High 39416027 39786998
2025 TRMT1L interacts with a component of the Rix1 ribosome biogenesis complex and binds to 28S rRNA as well as a subset of tRNAs, as determined by eCLIP-seq. eCLIP-seq Cell reports Medium 39416027 39786998
2025 Tyrosine and serine tRNAs are dependent upon m2,2G modifications for their stability and function in translation; human patient cells with disease-associated TRMT1 variants exhibit reduced levels of tyrosine and serine tRNAs. tRNA-seq in TRMT1L/TRMT1 knockout and patient-derived cell lines, translation functional assays Cell reports Medium 39786990
2006 Mouse Trm1-like (ortholog of human TRMT1L/C1orf25), when disrupted by gene-trap insertion in the first intron, causes significantly altered motor coordination and aberrant exploratory behaviour in viable mice, with expression detected in neural tissues including spinal ganglia, trigeminal nerve, olfactory epithelium, and brain nuclei during embryogenesis and in adult brain. Gene-trap mouse model, behavioral testing (motor coordination and exploratory behavior), LacZ reporter for expression mapping Gene Medium 17198746

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Genome-Wide Methylation Analysis Identifies NOX4 and KDM5A as Key Regulators in Inhibiting Breast Cancer Cell Proliferation by Ginsenoside Rg3. The American journal of Chinese medicine 35 30149757
2006 The mouse Trm1-like gene is expressed in neural tissues and plays a role in motor coordination and exploratory behaviour. Gene 25 17198746
2021 Subcellular relocalization and nuclear redistribution of the RNA methyltransferases TRMT1 and TRMT1L upon neuronal activation. RNA biology 15 33499731
2021 A novel 13 RNA binding proteins (RBPs) signature could predict prostate cancer biochemical recurrence. Pathology, research and practice 15 34419719
2025 Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs. Cell reports 14 39786990
2025 TRMT1L-catalyzed m22G27 on tyrosine tRNA is required for efficient mRNA translation and cell survival under oxidative stress. Cell reports 13 39786998
2024 A susceptibility gene signature for ERBB2-driven mammary tumour development and metastasis in collaborative cross mice. EBioMedicine 8 39067134
2026 Thermal stress responses and heat stress resilience genes in chickens are revealed through genomic and transcriptomic insights. Journal of animal science and biotechnology 1 41796331
2024 TRMT1L-catalyzed m2 2G27 on tyrosine tRNA is required for efficient mRNA translation and cell survival under oxidative stress. bioRxiv : the preprint server for biology 1 39416027
2026 Inflammation and Oxidative-Stress Pathways Are Associated with Idiopathic Sudden Hearing Loss: A Genome-Wide Association Study in 15,494 Japanese Individuals. International journal of molecular sciences 0 41751972

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