Affinage

TRMT1L

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

Round 2 corrected
Length
733 aa
Mass
81.7 kDa
Annotated
2026-04-28
40 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRMT1L is a tRNA methyltransferase that catalyzes N2,N2-dimethylguanosine (m2,2G) at position 27 of tRNA-Tyr-GUA and at position 26 of a subset of cytosolic tRNA-Ala(AGC) isodecoders, distinguishing it from the paralog TRMT1, which modifies position 26 across most G26-bearing tRNAs (PMID:33499731, PMID:39786990). Beyond its catalytic role, TRMT1L non-catalytically maintains acp3U and dihydrouridine modifications on tRNA-Tyr-GUA, tRNA-Cys-GCA, and tRNA-Ala-CGC, and its loss destabilizes tyrosine and serine tRNAs, impairs global translation, and confers hypersensitivity to oxidative stress (PMID:39786990, PMID:39786998). TRMT1L interacts with the Rix1 ribosome biogenesis complex and binds 28S rRNA, linking tRNA modification to ribosome-associated processes; in neurons it resides in nucleoli under basal conditions but relocalizes to nuclear puncta upon neuronal activation (PMID:39786998, PMID:33499731). Knockout mice display defective motor coordination and aberrant exploratory behavior, establishing a requirement for TRMT1L in postnatal neuronal function (PMID:17198746).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2006 Medium

    The first in vivo evidence that TRMT1L is required for normal brain function came from gene-trap knockout mice that displayed defective motor coordination and altered exploratory behavior, establishing that a predicted tRNA methyltransferase has an essential neuronal role.

    Evidence Gene-trap knockout mouse; LacZ reporter expression mapping; behavioral assays

    PMID:17198746

    Open questions at the time
    • Single-lab study without independent replication of behavioral phenotype
    • Enzymatic substrate of TRMT1L was not identified
    • Mechanism linking tRNA methylation to neuronal function unknown
  2. 2021 High

    Identification of cytosolic tRNA-Ala(AGC) isodecoders as TRMT1L substrates (m2,2G26) resolved the enzyme's first catalytic specificity and revealed that TRMT1L undergoes stimulus-specific nucleolar-to-punctate relocalization upon neuronal activation, suggesting a regulated role beyond constitutive tRNA modification.

    Evidence LC-MS/MS tRNA modification profiling in TRMT1L-KO mouse cells; live-cell imaging and immunofluorescence during LTP-mimicking neuronal activation

    PMID:33499731

    Open questions at the time
    • Identity and function of nuclear puncta upon neuronal activation uncharacterized
    • Whether m2,2G26 on tRNA-Ala(AGC) impacts translation was not tested
    • Relationship of TRMT1L to ribosome biogenesis unknown
  3. 2025 High

    Two concurrent studies resolved TRMT1L's primary catalytic substrate as m2,2G at position 27 of tRNA-Tyr-GUA (not position 26), identified a non-catalytic role in maintaining acp3U and dihydrouridine on multiple tRNAs, and demonstrated that TRMT1L loss destabilizes key tRNAs, reduces global translation, and sensitizes cells to oxidative stress; interaction with the Rix1 complex and 28S rRNA further connected TRMT1L to ribosome biogenesis.

    Evidence tRNA-seq, nanopore sequencing, eCLIP-seq, LC-MS/MS, translation assays, and oxidative stress survival assays in TRMT1L-KO and patient-derived cells (two independent labs)

    PMID:39786990 PMID:39786998

    Open questions at the time
    • Structural basis for position-27 specificity versus TRMT1's position-26 activity is unknown
    • Mechanism by which TRMT1L non-catalytically promotes acp3U/dihydrouridine deposition is unresolved
    • Functional significance of 28S rRNA binding and Rix1 complex interaction not tested in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • Open questions remain regarding the molecular mechanism of TRMT1L's non-catalytic influence on other tRNA modifications, the identity and function of the neuronal activation-induced nuclear puncta, and whether the translation and oxidative stress phenotypes causally underlie the neuronal deficits observed in knockout mice.
  • No structural model of TRMT1L bound to tRNA substrate
  • Causal link between tRNA modification loss and neuronal phenotype not established
  • Identity of the nuclear puncta formed upon neuronal activation remains unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3
Localization
GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-392499 Metabolism of proteins 2
Partners
PELP1
Complex memberships
Rix1 ribosome biogenesis complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Mouse Trm1-like (ortholog of human TRMT1L) is expressed in multiple neuronal structures during embryonic development (spinal ganglia, trigeminal nerve and ganglion, olfactory epithelium, thalamus, metencephalon, medulla oblongata) and persists in adult brain cortex and cerebellum. Knockout mice generated by gene-trap insertion show significantly altered motor coordination and aberrant exploratory behaviour, establishing a role for Trmt1-like in postnatal neuronal function. Gene-trap knockout mouse model; LacZ reporter for expression mapping; behavioral tests (motor coordination, exploratory behaviour assays) Gene Medium 17198746
2021 TRMT1L is responsible for methylating a subset of cytosolic tRNA-Ala(AGC) isodecoders at position 26 (m2,2G26), as demonstrated using knockout mouse models and LC-MS/MS. Under basal conditions TRMT1L resides predominantly in nucleoli; upon neuronal activation (mimicking long-term potentiation), TRMT1L relocalizes from nucleoli to small uncharacterized punctate compartments in the nucleus—a response that does not occur upon heat shock, indicating specificity for neuronal activation stimuli. Knockout mouse models, LC-MS/MS tRNA modification profiling, next-generation sequencing, live-cell imaging/immunofluorescence in neuronal activation model, patient-derived cell lines RNA biology High 33499731
2025 TRMT1L is the enzyme responsible for the N2,N2-dimethylguanosine (m2,2G) modification specifically at position 27 of tyrosine tRNAs (distinct from TRMT1 which modifies position 26 of all tRNAs bearing G26). 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. Loss of TRMT1L reduces tyrosine and serine tRNA stability and impairs their function in translation. Comprehensive tRNA sequencing (tRNA-seq) of TRMT1L/TRMT1 knockout and patient-derived cells, LC-MS/MS modification profiling, translation reporter assays Cell reports High 39786990
2025 TRMT1L interacts with a component of the Rix1 ribosome biogenesis complex and binds to 28S rRNA as well as a subset of tRNAs (identified by eCLIP-seq). TRMT1L catalyzes m2,2G solely at position 27 of tRNA-Tyr-GUA. TRMT1L depletion also impairs deposition of acp3U and dihydrouridine on tRNA-Tyr-GUA, tRNA-Cys-GCA, and tRNA-Ala-CGC. TRMT1L knockout causes a marked decrease in tRNA-Tyr-GUA levels, reduction in global translation rates, and hypersensitivity to oxidative stress. eCLIP-seq, nanopore tRNA-seq, TRMT1L knockout cells, global translation rate assays, oxidative stress survival assays Cell reports High 39786998
2024 Preprint version confirming TRMT1L catalyzes m2,2G at position 27 of tRNA-Tyr-GUA, interacts with the Rix1 ribosome biogenesis complex and 28S rRNA, and that its loss impairs acp3U/dihydrouridine deposition on multiple tRNAs and reduces global translation with hypersensitivity to oxidative stress. eCLIP-seq, Nanopore tRNA-seq, TRMT1L KO cells, translation assays bioRxivpreprint High 39416027

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2005 Nucleolar proteome dynamics. Nature 934 15635413
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. Journal of proteome research 422 20020773
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2017 A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis. Molecular cell 248 28431233
2009 An integrated workflow for charting the human interaction proteome: insights into the PP2A system. Molecular systems biology 223 19156129
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2020 Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Molecular cell 159 32416067
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2020 Comparative Application of BioID and TurboID for Protein-Proximity Biotinylation. Cells 146 32344865
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2007 Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach. Cell cycle (Georgetown, Tex.) 127 17314511
2022 Human transcription factor protein interaction networks. Nature communications 123 35140242
2022 The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin. Nature cell biology 122 35013556
2015 Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes. Molecular systems biology 120 25609649
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 6 39067134
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
2026 Thermal stress responses and heat stress resilience genes in chickens are revealed through genomic and transcriptomic insights. Journal of animal science and biotechnology 0 41796331