{"gene":"TRMT112","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2019,"finding":"METTL5 must form a heterodimeric complex with TRMT112 to gain metabolic stability in cells; the METTL5-TRMT112 complex is responsible for N6-methyladenosine (m6A) modification of 18S rRNA, and the first atomic resolution structure of METTL5-TRMT112 was determined, revealing an RNA-binding mode distinct from other m6A methyltransferases and suggesting an adenosine extrusion mechanism.","method":"Co-immunoprecipitation, crystal structure determination, in vivo stability assays, rRNA modification mapping","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vivo functional validation, replicated by subsequent studies","pmids":["31328227"],"is_preprint":false},{"year":2015,"finding":"Human WBSCR22 (Bud23 ortholog) forms a complex with TRMT112 to methylate G in 18S rRNA and is required for pre-rRNA processing leading to 18S rRNA synthesis; importantly, ribosome biogenesis requires the presence of the methyltransferase rather than its catalytic activity, indicating a quality control role for TRMT112-dependent methyltransferase binding to nascent pre-rRNAs.","method":"Functional complementation assays, pre-rRNA processing analysis, catalytic mutant studies in human cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, replicated across yeast and human systems","pmids":["25851604"],"is_preprint":false},{"year":2014,"finding":"Bud23-Trm112 (yeast ortholog complex) catalyzes N7-methylguanosine at position G1575 of 18S rRNA; crystal structures of apo and SAM-bound forms show Bud23 and Trm112 interact via a β-zipper involving main-chain atoms, burying a hydrophobic surface; Trm112 undergoes induced fit to accommodate Bud23; m7G methylation occurs at a late step of small subunit biogenesis despite early recruitment; Bud23-Trm112 interacts directly with the DEAH helicase Dhr1.","method":"Crystal structure determination (apo and SAM-bound), site-directed mutagenesis, co-immunoprecipitation, sucrose gradient sedimentation, in vivo methylation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and multiple functional validations","pmids":["25489090"],"is_preprint":false},{"year":2012,"finding":"In S. cerevisiae, Trm112 is required for efficient ribosome synthesis and mitosis progression; Trm112 interacts directly with Bud23 in vitro and is required for Bud23 stability in vivo; without Trm112, Bud23-mediated 18S rRNA methylation at G1575 is lost, Bud23 fails to bind nascent preribosomes, and a nucleolar surveillance pathway involving TRAMP complexes degrades preribosomes.","method":"In vitro binding assay, co-purification with pre-rRNAs, in vivo stability assays, methylation assays, genetic deletion analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro and in vivo orthogonal methods establishing mechanism","pmids":["22493060"],"is_preprint":false},{"year":2011,"finding":"The Mtq2-Trm112 holoenzyme methylates the glutamine of the GGQ motif in eukaryotic translation termination factor eRF1; crystal structure of Mtq2-Trm112 complex was determined and active site mapped; Trm112 uses a common structural strategy to activate Mtq2, Trm9, and Trm11 methyltransferases despite their low sequence identity (<20%).","method":"Crystal structure determination, site-directed mutagenesis, in vivo functional experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and functional validation","pmids":["21478168"],"is_preprint":false},{"year":2012,"finding":"Trm112 is required for both small (40S) and large (60S) ribosomal subunit biogenesis in yeast; Trm112 stabilizes free methyltransferase partners not engaged with substrate; Trm112 also interacts with Nop2 and Rcm1, which are linked to 60S biogenesis.","method":"Sucrose gradient sedimentation, co-immunoprecipitation, genetic suppression analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and genetic epistasis with defined phenotypic readouts","pmids":["22956767"],"is_preprint":false},{"year":2015,"finding":"TRMT112 is the interaction partner of WBSCR22 in human cells; knockdown of TRMT112 decreases WBSCR22 protein levels; TRMT112 determines the nuclear localization of WBSCR22; WBSCR22 is ubiquitinated and degraded via the proteasome pathway when not stabilized by TRMT112.","method":"SILAC-coupled co-immunoprecipitation, siRNA knockdown, subcellular fractionation/localization imaging, ubiquitination assay, proteasome inhibitor treatment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (SILAC-Co-IP, KD, localization, ubiquitination assay)","pmids":["26214185"],"is_preprint":false},{"year":2017,"finding":"Trm112 activates the Trm11-Trm112 complex by influencing S-adenosyl-L-methionine (SAM) binding and contributing to tRNA binding; all Trm112-dependent methyltransferases compete to interact with Trm112 through similar molecular interfaces.","method":"Enzymatic activity assays, hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), SAM-binding experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 — HDX-MS structural data plus enzymatic activity assays","pmids":["27986851"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Trm9-Trm112 complex reveals structural plasticity allowing Trm112 to interact similarly with multiple methyltransferase partners despite low sequence identity; Trm9-Trm112 modifies the tRNA anticodon wobble position (mcm5U modification) to promote translational fidelity.","method":"Crystal structure determination, structure-function analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation","pmids":["26438534"],"is_preprint":false},{"year":2021,"finding":"THUMPD3 interacts with TRMT112 to form an active tRNA m2G methyltransferase; THUMPD3 alone cannot modify tRNAs but THUMPD3-TRMT112 together methylate the 2-amino group of G at position 6 (and G7 in tRNATrp) of 26 tested G6-containing human cytoplasmic tRNAs, recognizing the 3'-CCA terminus of mature tRNAs; THUMPD3 knockout impairs global protein synthesis and reduces cell growth.","method":"Reverse genetics, RNA-mass spectrometry, in vitro enzymatic assay, co-immunoprecipitation, knockout cell line analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution plus KO phenotype and multiple orthogonal methods","pmids":["34669960"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of human N6AMT1 (HEMK2)-TRMT112 complex bound to SAM shows Trm112 binds a hydrophobic surface of N6AMT1 to stabilize its structure without directly contributing to substrate binding or catalysis; biochemical data confirm the complex has no DNA methyltransferase activity but methylates Gln185 of eRF1, establishing N6AMT1 as a protein glutamine methyltransferase.","method":"Crystal structure determination, DNA binding assays, in vitro methyltransferase activity assays","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vitro biochemical validation","pmids":["31636962"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of HEMK2 (N6AMT1)-TRMT112 complexes (SAM-bound and post-catalytic SAH/methylglutamine-bound) reveals a specific pocket in HEMK2 for accommodating glutamine substrate and catalyzing methylation; HEMK2 can methylate both lysine and glutamine residues.","method":"Crystal structure determination, mass spectrometry, in vitro methylation assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of substrate complex with mass spectrometry validation","pmids":["32969463"],"is_preprint":false},{"year":2018,"finding":"In archaea (Haloferax volcanii), Trm112 orthologs interact with and activate multiple methyltransferases targeting translation machinery components, extending the Trm112 methyltransferase activation network beyond eukaryotes to include archaeal partners, some orthologous to eukaryotic partners and others similar to bacterial methyltransferases.","method":"Functional and structural characterization, interaction network mapping, native mass spectrometry","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods but in archaeal model system","pmids":["30010922"],"is_preprint":false},{"year":2021,"finding":"Human TRMT112 interacts with seven methyltransferases (N6AMT1, WBSCR22, METTL5, ALKBH8, THUMPD2, THUMPD3, TRMT11) identified by SILAC screen; TRMT112 stabilizes all seven MTases in cells; a strong mutual feedback loop exists between TRMT112 and its MTase partners; single amino acid mutations on TRMT112 surface reveal differential interaction requirements.","method":"SILAC co-immunoprecipitation, co-expression stability assays, site-directed mutagenesis","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — SILAC-MS interactome with mutagenesis and stability assays across all partners","pmids":["34948388"],"is_preprint":false},{"year":2022,"finding":"The METTL5-TRMT112 complex installs the m6A modification at position 1832 of human 18S rRNA; TRMT112 is required for METTL5 stability; METTL5 mutations associated with microcephaly/intellectual disability disrupt the METTL5-TRMT112 interaction; loss of METTL5 regulates gene expression at the translational level.","method":"Methyltransferase activity assays, co-immunoprecipitation, rRNA modification mapping, polysome profiling, mouse knockout studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic assays plus KO mouse model and multiple orthogonal approaches","pmids":["35033535"],"is_preprint":false},{"year":2021,"finding":"BUD23-TRMT112 complex mediates chromosomal tethering of Borna disease virus 1 (BoDV-1) viral ribonucleoproteins (vRNPs); TRMT112 binds BoDV-1 L protein at the RNA-dependent RNA polymerase domain together with BUD23; the MTase activity of BUD23-TRMT112 is necessary for this chromosomal tethering.","method":"Proximity-dependent biotinylation, co-immunoprecipitation, chromosomal tethering assays, catalytic mutant analysis","journal":"Microbiology and immunology","confidence":"Medium","confidence_rationale":"Tier 2 — proximity labeling plus functional tethering assays with mechanistic follow-up","pmids":["34324219"],"is_preprint":false},{"year":2019,"finding":"TRMT112 regulates the expression of N6AMT1 isoforms: only isoform 1 (with intact substrate binding motif) can interact with TRMT112; the alternatively spliced isoform 2 (lacking substrate binding motif) cannot interact with TRMT112 and is rapidly degraded, establishing TRMT112 as part of a cellular quality control mechanism.","method":"Co-immunoprecipitation, protein stability assays, siRNA knockdown, isoform expression analysis","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, Co-IP and stability assays","pmids":["31466382"],"is_preprint":false},{"year":2026,"finding":"Covalent stereoprobes react selectively with C100 of TRMT112 only when TRMT112 is complexed with METTL5 (not other MT partners); a co-crystal structure reveals stereoprobe binding to a composite pocket templated by METTL5 and absent in other TRMT112:MT complexes; stereoprobe binding causes allosteric agonism of METTL5, demonstrating that TRMT112's C100 is part of a partner-specific composite binding site.","method":"Chemical proteomics, co-crystal structure determination, covalent probe reactivity assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus chemical proteomics and functional agonism assay","pmids":["41507545"],"is_preprint":false},{"year":2022,"finding":"In yeast, the Trm11-Trm112 complex requires the CCA terminus of mature tRNA, a G10-C25 base pair, a regular-size variable region, and specific anticodon loop features for m2G10 methylation; precursor tRNA is not a substrate.","method":"In vitro methylation assays with 60 tRNA transcript variants, purification of tRNA from wild-type and deletion strains","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 — systematic in vitro substrate specificity determination with in vivo validation","pmids":["35409407"],"is_preprint":false},{"year":2026,"finding":"THUMPD3-TRMT112 complex promotes TFEB translation via m2G modification of tRNALeu(CAG); deficiency of THUMPD3/TRMT112 suppresses TFEB translation, reduces autophagic flux, and inhibits pancreatic cancer cell growth.","method":"Knockdown experiments, polysome profiling, in vivo xenograft, autophagic flux assays, mechanistic tRNA modification analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic link between tRNA modification and specific translational target with in vivo validation","pmids":["41530782"],"is_preprint":false}],"current_model":"TRMT112 is a small, evolutionarily conserved 'hub' protein that functions as an obligate activating co-factor for at least seven methyltransferases (METTL5, WBSCR22/BUD23, N6AMT1/HEMK2, TRMT11, THUMPD3, THUMPD2, ALKBH8) by forming stable heterodimeric complexes through a conserved β-zipper/hydrophobic interface, stabilizing each partner against proteasomal degradation and, in several cases, directly contributing to substrate (SAM, RNA, or protein) binding; through these complexes TRMT112 orchestrates methylation of 18S rRNA (m6A via METTL5, m7G via WBSCR22), tRNAs (m2G6/7 via THUMPD3, m2G10 via TRMT11, mcm5U via ALKBH8/Trm9 in yeast), and protein translation factors (Gln185 methylation of eRF1 via N6AMT1/Mtq2), thereby coordinating the maturation of all major components of the translation apparatus."},"narrative":{"teleology":[{"year":2011,"claim":"Determining how TRMT112 activates structurally diverse methyltransferases, the crystal structure of yeast Mtq2–Trm112 established that TRMT112 uses a single conserved binding mode to activate partners with less than 20% sequence identity, directly enabling Gln methylation of translation termination factor eRF1.","evidence":"Crystal structure of Mtq2–Trm112 with site-directed mutagenesis and in vivo functional assays in yeast","pmids":["21478168"],"confidence":"High","gaps":["No structural basis for how TRMT112 discriminates among multiple partners","Mammalian Mtq2/N6AMT1 complex not yet structurally resolved at this point"]},{"year":2012,"claim":"Establishing TRMT112 as essential for ribosome biogenesis, loss of Trm112 in yeast abolished Bud23-mediated 18S rRNA m7G1575 modification, destabilized Bud23 protein, prevented its recruitment to pre-ribosomes, and triggered nucleolar surveillance-mediated preribosome degradation, revealing TRMT112 as a stabilizer and recruitment factor for its partners.","evidence":"In vitro binding, in vivo stability assays, co-purification with pre-rRNAs, and methylation assays in S. cerevisiae deletion strains","pmids":["22493060","22956767"],"confidence":"High","gaps":["Whether TRMT112 has partners outside the methyltransferase family","How TRMT112 partitions among competing partners in vivo"]},{"year":2014,"claim":"Resolving the atomic architecture of the rRNA methyltransferase complex, crystal structures of Bud23–Trm112 in apo and SAM-bound states revealed the β-zipper interface mechanism and showed Trm112 undergoes induced fit upon partner binding, explaining its structural plasticity.","evidence":"Crystal structures (apo and SAM-bound), mutagenesis, sucrose gradient sedimentation, and co-IP in yeast","pmids":["25489090"],"confidence":"High","gaps":["Whether the induced-fit mechanism generalizes to all TRMT112 partners","No structure of TRMT112 bound to an RNA substrate"]},{"year":2015,"claim":"Extending the mechanism to human cells, TRMT112 was shown to determine the nuclear localization and protein stability of WBSCR22, which is ubiquitinated and degraded by the proteasome when not stabilized by TRMT112; ribosome biogenesis required WBSCR22 presence rather than catalytic activity, indicating a quality-control checkpoint function.","evidence":"SILAC-Co-IP, siRNA knockdown, subcellular fractionation, ubiquitination assays, and catalytic-dead mutant analysis in human cells; crystal structure of yeast Trm9–Trm112","pmids":["26214185","25851604","26438534"],"confidence":"High","gaps":["How TRMT112 shields partners from ubiquitin ligases","Identity of the E3 ligase targeting free methyltransferase partners"]},{"year":2017,"claim":"Addressing how TRMT112 activates tRNA methyltransferases, HDX-MS and enzymatic assays showed that Trm112 enhances SAM cofactor binding and contributes to tRNA recognition in the Trm11–Trm112 complex, and that all Trm112-dependent methyltransferases compete for the same molecular interface.","evidence":"HDX-MS, SAM-binding assays, and enzymatic activity measurements with purified yeast complexes","pmids":["27986851"],"confidence":"High","gaps":["In vivo stoichiometry and kinetic hierarchy of partner competition","Whether post-translational modifications regulate partner preference"]},{"year":2019,"claim":"Identifying TRMT112 as essential for 18S rRNA m6A modification, the METTL5–TRMT112 crystal structure revealed an RNA-binding mode distinct from other m6A writers with an adenosine extrusion mechanism; separately, the human N6AMT1–TRMT112 structure confirmed the complex is a protein glutamine methyltransferase (not a DNA methyltransferase).","evidence":"Crystal structures, co-IP, rRNA modification mapping, in vitro methyltransferase assays, and protein stability assays in human cells","pmids":["31328227","31636962"],"confidence":"High","gaps":["No RNA-bound co-crystal structure of METTL5–TRMT112","How the complex is recruited to 18S rRNA in vivo"]},{"year":2021,"claim":"Defining the full human TRMT112 interactome, SILAC proteomics identified seven methyltransferase partners (N6AMT1, WBSCR22, METTL5, ALKBH8, THUMPD2, THUMPD3, TRMT11), all stabilized by TRMT112 with a mutual feedback loop; THUMPD3–TRMT112 was shown to be an active tRNA m2G6/7 methyltransferase whose loss impairs global protein synthesis.","evidence":"SILAC-Co-IP, mutagenesis, co-expression stability assays, RNA-MS, in vitro enzymatic assays, knockout cell analysis","pmids":["34948388","34669960"],"confidence":"High","gaps":["Whether additional partners exist beyond the seven identified","Structural basis of THUMPD3–TRMT112 substrate recognition"]},{"year":2022,"claim":"Refining substrate specificity rules, the Trm11–Trm112 complex was shown to require mature tRNA features (CCA terminus, G10–C25 base pair, regular variable region) for m2G10 modification, excluding pre-tRNAs as substrates; METTL5 mutations causing microcephaly/intellectual disability were found to disrupt the METTL5–TRMT112 interaction.","evidence":"Systematic in vitro methylation with 60 tRNA variants in yeast; METTL5 disease-mutation analysis with co-IP and rRNA modification mapping in human cells and mouse models","pmids":["35409407","35033535"],"confidence":"High","gaps":["Whether TRMT112 dysfunction alone causes human disease","Tissue-specific consequences of individual partner loss"]},{"year":2026,"claim":"Demonstrating partner-specific druggability, covalent stereoprobes were found to react selectively with TRMT112 C100 only when complexed with METTL5, exploiting a composite pocket absent in other TRMT112 complexes; separately, THUMPD3–TRMT112 was linked to TFEB translational control and autophagy regulation in pancreatic cancer.","evidence":"Chemical proteomics with co-crystal structure of stereoprobe-bound METTL5–TRMT112; knockdown, polysome profiling, xenograft models for THUMPD3–TRMT112 in pancreatic cancer","pmids":["41507545","41530782"],"confidence":"High","gaps":["Whether allosteric agonism of METTL5 by stereoprobes alters cellular rRNA methylation","Broader translational targets beyond TFEB controlled by THUMPD3–TRMT112"]},{"year":null,"claim":"Key unresolved questions include how TRMT112 is partitioned among its seven competing partners in vivo, whether TRMT112 loss-of-function mutations directly cause human Mendelian disease, and the structural basis for TRMT112 complexes with THUMPD2, THUMPD3, and ALKBH8.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vivo quantitative model of partner competition and stoichiometry","No human disease mutations mapped to TRMT112 itself","No crystal structures of TRMT112 with THUMPD2, THUMPD3, or ALKBH8"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,7,13]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[3,6,13]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,9,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,10,11]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,3,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[19]}],"complexes":["METTL5-TRMT112","WBSCR22/BUD23-TRMT112","N6AMT1/HEMK2-TRMT112","THUMPD3-TRMT112"],"partners":["METTL5","WBSCR22","N6AMT1","TRMT11","THUMPD3","THUMPD2","ALKBH8"],"other_free_text":[]},"mechanistic_narrative":"TRMT112 is an evolutionarily conserved obligate co-factor that activates at least seven methyltransferases—METTL5, WBSCR22/BUD23, N6AMT1/HEMK2, TRMT11, THUMPD3, THUMPD2, and ALKBH8—by forming stable heterodimeric complexes through a conserved β-zipper/hydrophobic interface, thereby coordinating methylation of rRNA, tRNA, and translation termination factors [PMID:21478168, PMID:26438534, PMID:34948388]. TRMT112 stabilizes each partner against ubiquitin–proteasome-dependent degradation, and in several complexes it directly contributes to SAM cofactor or RNA substrate binding; different methyltransferase partners compete for a shared interaction surface on TRMT112 [PMID:27986851, PMID:26214185, PMID:31328227]. Through these partnerships, TRMT112 controls 18S rRNA m6A (via METTL5) and m7G (via WBSCR22) modifications required for ribosome biogenesis, tRNA m2G modifications at positions 6/7 (via THUMPD3) and 10 (via TRMT11) that promote translational fidelity and efficiency, and glutamine methylation of eRF1 (via N6AMT1) needed for translation termination [PMID:35033535, PMID:34669960, PMID:31636962, PMID:25489090]. Loss of THUMPD3–TRMT112-dependent tRNA modification suppresses TFEB translation and autophagic flux, linking TRMT112's methyltransferase-activating function to downstream cellular programs including autophagy and cell growth [PMID:41530782]."},"prefetch_data":{"uniprot":{"accession":"Q9UI30","full_name":"Multifunctional methyltransferase subunit TRM112-like protein","aliases":["tRNA methyltransferase 112 homolog"],"length_aa":125,"mass_kda":14.2,"function":"Acts as an activator of both rRNA/tRNA and protein methyltransferases (PubMed:18539146, PubMed:20308323, PubMed:25851604, PubMed:31061526, PubMed:31328227, PubMed:31636962, PubMed:37283053). Together with methyltransferase BUD23, methylates the N(7) position of a guanine in 18S rRNA (PubMed:25851604). The heterodimer with N6AMT1/HEMK2 catalyzes N5-methylation of ETF1 on 'Gln-185', using S-adenosyl L-methionine as methyl donor (PubMed:18539146, PubMed:31061526, PubMed:31636962). The heterodimer with N6AMT1/HEMK2 also monomethylates 'Lys-12' of histone H4 (H4K12me1) (PubMed:31061526). The heterodimer with ALKBH8 catalyzes the methylation of 5-carboxymethyl uridine to 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in target tRNA species (PubMed:20308323). Together with methyltransferase THUMPD3, catalyzes the formation of N(2)-methylguanosine at position 6 in a broad range of tRNA substrates and at position 7 of tRNA(Trp) (PubMed:34669960, PubMed:37283053). Involved in the pre-rRNA processing steps leading to small-subunit rRNA production (PubMed:25851604). Together with methyltransferase METTL5, specifically methylates the 6th position of adenine in position 1832 of 18S rRNA (PubMed:31328227, PubMed:33428944, PubMed:35033535, PubMed:37283053)","subcellular_location":"Nucleus, nucleoplasm; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q9UI30/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TRMT112","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FAM207A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRMT112","total_profiled":1310},"omim":[{"mim_id":"621532","title":"THUMP DOMAIN PROTEIN 3, tRNA GUANOSINE METHYLTRANSFERASE; THUMPD3","url":"https://www.omim.org/entry/621532"},{"mim_id":"621531","title":"tRNA METHYLTRANSFERASE 11; TRMT11","url":"https://www.omim.org/entry/621531"},{"mim_id":"618630","title":"tRNA METHYLTRANSFERASE SUBUNIT 11-2; TRMT112","url":"https://www.omim.org/entry/618630"},{"mim_id":"618628","title":"METHYLTRANSFERASE 5, N6-ADENOSINE; METTL5","url":"https://www.omim.org/entry/618628"},{"mim_id":"615733","title":"rRNA METHYLTRANSFERASE AND RIBOSOME MATURATION FACTOR BUD23; BUD23","url":"https://www.omim.org/entry/615733"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRMT112"},"hgnc":{"alias_symbol":["HSPC152","HSPC170","TRM112","TRMT11-2","hTrm112"],"prev_symbol":[]},"alphafold":{"accession":"Q9UI30","domains":[{"cath_id":"2.20.25.10","chopping":"2-117","consensus_level":"high","plddt":94.2036,"start":2,"end":117}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI30","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI30-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI30-F1-predicted_aligned_error_v6.png","plddt_mean":92.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRMT112","jax_strain_url":"https://www.jax.org/strain/search?query=TRMT112"},"sequence":{"accession":"Q9UI30","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UI30.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UI30/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI30"}},"corpus_meta":[{"pmid":"31328227","id":"PMC_31328227","title":"The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31328227","citation_count":416,"is_preprint":false},{"pmid":"25851604","id":"PMC_25851604","title":"The human 18S rRNA base methyltransferases DIMT1L and WBSCR22-TRMT112 but not rRNA modification are required for ribosome biogenesis.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25851604","citation_count":140,"is_preprint":false},{"pmid":"25489090","id":"PMC_25489090","title":"Structural and functional studies of Bud23-Trm112 reveal 18S rRNA N7-G1575 methylation occurs on late 40S precursor ribosomes.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25489090","citation_count":84,"is_preprint":false},{"pmid":"22493060","id":"PMC_22493060","title":"Trm112 is required for Bud23-mediated methylation of the 18S rRNA at position G1575.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22493060","citation_count":75,"is_preprint":false},{"pmid":"21478168","id":"PMC_21478168","title":"Mechanism of activation of methyltransferases involved in translation by the Trm112 'hub' protein.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21478168","citation_count":66,"is_preprint":false},{"pmid":"35033535","id":"PMC_35033535","title":"The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35033535","citation_count":60,"is_preprint":false},{"pmid":"28134793","id":"PMC_28134793","title":"Trm112, a Protein Activator of Methyltransferases Modifying Actors of the Eukaryotic Translational Apparatus.","date":"2017","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/28134793","citation_count":49,"is_preprint":false},{"pmid":"34669960","id":"PMC_34669960","title":"THUMPD3-TRMT112 is a m2G methyltransferase working on a broad range of tRNA substrates.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34669960","citation_count":49,"is_preprint":false},{"pmid":"31636962","id":"PMC_31636962","title":"Structural insight into human N6amt1-Trm112 complex functioning as a protein methyltransferase.","date":"2019","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/31636962","citation_count":38,"is_preprint":false},{"pmid":"30010922","id":"PMC_30010922","title":"Evolutionary insights into Trm112-methyltransferase holoenzymes involved in translation between archaea and eukaryotes.","date":"2018","source":"Nucleic acids 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/22956767","citation_count":31,"is_preprint":false},{"pmid":"27986851","id":"PMC_27986851","title":"Activation mode of the eukaryotic m2G10 tRNA methyltransferase Trm11 by its partner protein Trm112.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27986851","citation_count":31,"is_preprint":false},{"pmid":"35088887","id":"PMC_35088887","title":"WBSCR22 and TRMT112 synergistically suppress cell proliferation, invasion and tumorigenesis in pancreatic cancer via transcriptional regulation of ISG15.","date":"2022","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35088887","citation_count":30,"is_preprint":false},{"pmid":"26214185","id":"PMC_26214185","title":"The Stability of Ribosome Biogenesis Factor WBSCR22 Is Regulated by Interaction with TRMT112 via Ubiquitin-Proteasome Pathway.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26214185","citation_count":29,"is_preprint":false},{"pmid":"34948388","id":"PMC_34948388","title":"Human TRMT112-Methyltransferase Network Consists of Seven Partners Interacting with a Common Co-Factor.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34948388","citation_count":23,"is_preprint":false},{"pmid":"31466382","id":"PMC_31466382","title":"The Common Partner of Several Methyltransferases TRMT112 Regulates the Expression of N6AMT1 Isoforms in Mammalian Cells.","date":"2019","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/31466382","citation_count":14,"is_preprint":false},{"pmid":"19749381","id":"PMC_19749381","title":"Production of yeast (m2G10) methyltransferase (Trm11 and Trm112 complex) in a wheat germ cell-free translation system.","date":"2009","source":"Nucleic acids symposium series (2004)","url":"https://pubmed.ncbi.nlm.nih.gov/19749381","citation_count":13,"is_preprint":false},{"pmid":"36081672","id":"PMC_36081672","title":"Pan-Cancer Analysis Reveals the Relation between TRMT112 and Tumor Microenvironment.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36081672","citation_count":12,"is_preprint":false},{"pmid":"33035335","id":"PMC_33035335","title":"Structural and functional insights into Archaeoglobus fulgidus m2G10 tRNA methyltransferase Trm11 and its Trm112 activator.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33035335","citation_count":11,"is_preprint":false},{"pmid":"34324219","id":"PMC_34324219","title":"BUD23-TRMT112 interacts with the L protein of Borna disease virus and mediates the chromosomal tethering of viral ribonucleoproteins.","date":"2021","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34324219","citation_count":11,"is_preprint":false},{"pmid":"32969463","id":"PMC_32969463","title":"Structural insight into HEMK2-TRMT112-mediated glutamine methylation.","date":"2020","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/32969463","citation_count":8,"is_preprint":false},{"pmid":"35409407","id":"PMC_35409407","title":"Required Elements in tRNA for Methylation by the Eukaryotic tRNA (Guanine-N2-) Methyltransferase (Trm11-Trm112 Complex).","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35409407","citation_count":7,"is_preprint":false},{"pmid":"41507545","id":"PMC_41507545","title":"Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5.","date":"2026","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/41507545","citation_count":2,"is_preprint":false},{"pmid":"41235342","id":"PMC_41235342","title":"Multiomic Landscape Uncovers TRMT112 as a Central Driver of HPV-Positive Head and Neck Squamous Cell Carcinoma.","date":"2025","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41235342","citation_count":1,"is_preprint":false},{"pmid":"40475643","id":"PMC_40475643","title":"Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40475643","citation_count":1,"is_preprint":false},{"pmid":"41530782","id":"PMC_41530782","title":"tRNA m2G methyltransferase complex THUMPD3-TRMT112 promotes pancreatic cancer progression and autophagy via modulating TFEB translation.","date":"2026","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41530782","citation_count":0,"is_preprint":false},{"pmid":"41507361","id":"PMC_41507361","title":"TRMT112 drives a tumor growth and metastasis-promoting program in triple-negative breast cancer.","date":"2026","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/41507361","citation_count":0,"is_preprint":false},{"pmid":"41551838","id":"PMC_41551838","title":"High expression of TRMT112 is associated with the development of oral squamous cell carcinoma.","date":"2026","source":"Journal of oral biology and craniofacial research","url":"https://pubmed.ncbi.nlm.nih.gov/41551838","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.13.670177","title":"Inhibition of <i>Clostridioides difficile-</i>specific DNA adenine methyltransferase CamA by analogs of <i>S</i>-adenosyl-L-methionine","date":"2025-08-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.13.670177","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.24.620129","title":"<i>Mettl5</i>  coordinates protein production and degradation of PERIOD to regulate sleep in  <i>Drosophila</i>","date":"2024-10-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.24.620129","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15971,"output_tokens":4766,"usd":0.059701},"stage2":{"model":"claude-opus-4-6","input_tokens":8269,"output_tokens":3170,"usd":0.180893},"total_usd":0.240594,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"METTL5 must form a heterodimeric complex with TRMT112 to gain metabolic stability in cells; the METTL5-TRMT112 complex is responsible for N6-methyladenosine (m6A) modification of 18S rRNA, and the first atomic resolution structure of METTL5-TRMT112 was determined, revealing an RNA-binding mode distinct from other m6A methyltransferases and suggesting an adenosine extrusion mechanism.\",\n      \"method\": \"Co-immunoprecipitation, crystal structure determination, in vivo stability assays, rRNA modification mapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vivo functional validation, replicated by subsequent studies\",\n      \"pmids\": [\"31328227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human WBSCR22 (Bud23 ortholog) forms a complex with TRMT112 to methylate G in 18S rRNA and is required for pre-rRNA processing leading to 18S rRNA synthesis; importantly, ribosome biogenesis requires the presence of the methyltransferase rather than its catalytic activity, indicating a quality control role for TRMT112-dependent methyltransferase binding to nascent pre-rRNAs.\",\n      \"method\": \"Functional complementation assays, pre-rRNA processing analysis, catalytic mutant studies in human cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, replicated across yeast and human systems\",\n      \"pmids\": [\"25851604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Bud23-Trm112 (yeast ortholog complex) catalyzes N7-methylguanosine at position G1575 of 18S rRNA; crystal structures of apo and SAM-bound forms show Bud23 and Trm112 interact via a β-zipper involving main-chain atoms, burying a hydrophobic surface; Trm112 undergoes induced fit to accommodate Bud23; m7G methylation occurs at a late step of small subunit biogenesis despite early recruitment; Bud23-Trm112 interacts directly with the DEAH helicase Dhr1.\",\n      \"method\": \"Crystal structure determination (apo and SAM-bound), site-directed mutagenesis, co-immunoprecipitation, sucrose gradient sedimentation, in vivo methylation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and multiple functional validations\",\n      \"pmids\": [\"25489090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In S. cerevisiae, Trm112 is required for efficient ribosome synthesis and mitosis progression; Trm112 interacts directly with Bud23 in vitro and is required for Bud23 stability in vivo; without Trm112, Bud23-mediated 18S rRNA methylation at G1575 is lost, Bud23 fails to bind nascent preribosomes, and a nucleolar surveillance pathway involving TRAMP complexes degrades preribosomes.\",\n      \"method\": \"In vitro binding assay, co-purification with pre-rRNAs, in vivo stability assays, methylation assays, genetic deletion analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro and in vivo orthogonal methods establishing mechanism\",\n      \"pmids\": [\"22493060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Mtq2-Trm112 holoenzyme methylates the glutamine of the GGQ motif in eukaryotic translation termination factor eRF1; crystal structure of Mtq2-Trm112 complex was determined and active site mapped; Trm112 uses a common structural strategy to activate Mtq2, Trm9, and Trm11 methyltransferases despite their low sequence identity (<20%).\",\n      \"method\": \"Crystal structure determination, site-directed mutagenesis, in vivo functional experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and functional validation\",\n      \"pmids\": [\"21478168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Trm112 is required for both small (40S) and large (60S) ribosomal subunit biogenesis in yeast; Trm112 stabilizes free methyltransferase partners not engaged with substrate; Trm112 also interacts with Nop2 and Rcm1, which are linked to 60S biogenesis.\",\n      \"method\": \"Sucrose gradient sedimentation, co-immunoprecipitation, genetic suppression analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and genetic epistasis with defined phenotypic readouts\",\n      \"pmids\": [\"22956767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRMT112 is the interaction partner of WBSCR22 in human cells; knockdown of TRMT112 decreases WBSCR22 protein levels; TRMT112 determines the nuclear localization of WBSCR22; WBSCR22 is ubiquitinated and degraded via the proteasome pathway when not stabilized by TRMT112.\",\n      \"method\": \"SILAC-coupled co-immunoprecipitation, siRNA knockdown, subcellular fractionation/localization imaging, ubiquitination assay, proteasome inhibitor treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (SILAC-Co-IP, KD, localization, ubiquitination assay)\",\n      \"pmids\": [\"26214185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Trm112 activates the Trm11-Trm112 complex by influencing S-adenosyl-L-methionine (SAM) binding and contributing to tRNA binding; all Trm112-dependent methyltransferases compete to interact with Trm112 through similar molecular interfaces.\",\n      \"method\": \"Enzymatic activity assays, hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), SAM-binding experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — HDX-MS structural data plus enzymatic activity assays\",\n      \"pmids\": [\"27986851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Trm9-Trm112 complex reveals structural plasticity allowing Trm112 to interact similarly with multiple methyltransferase partners despite low sequence identity; Trm9-Trm112 modifies the tRNA anticodon wobble position (mcm5U modification) to promote translational fidelity.\",\n      \"method\": \"Crystal structure determination, structure-function analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation\",\n      \"pmids\": [\"26438534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"THUMPD3 interacts with TRMT112 to form an active tRNA m2G methyltransferase; THUMPD3 alone cannot modify tRNAs but THUMPD3-TRMT112 together methylate the 2-amino group of G at position 6 (and G7 in tRNATrp) of 26 tested G6-containing human cytoplasmic tRNAs, recognizing the 3'-CCA terminus of mature tRNAs; THUMPD3 knockout impairs global protein synthesis and reduces cell growth.\",\n      \"method\": \"Reverse genetics, RNA-mass spectrometry, in vitro enzymatic assay, co-immunoprecipitation, knockout cell line analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution plus KO phenotype and multiple orthogonal methods\",\n      \"pmids\": [\"34669960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of human N6AMT1 (HEMK2)-TRMT112 complex bound to SAM shows Trm112 binds a hydrophobic surface of N6AMT1 to stabilize its structure without directly contributing to substrate binding or catalysis; biochemical data confirm the complex has no DNA methyltransferase activity but methylates Gln185 of eRF1, establishing N6AMT1 as a protein glutamine methyltransferase.\",\n      \"method\": \"Crystal structure determination, DNA binding assays, in vitro methyltransferase activity assays\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro biochemical validation\",\n      \"pmids\": [\"31636962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of HEMK2 (N6AMT1)-TRMT112 complexes (SAM-bound and post-catalytic SAH/methylglutamine-bound) reveals a specific pocket in HEMK2 for accommodating glutamine substrate and catalyzing methylation; HEMK2 can methylate both lysine and glutamine residues.\",\n      \"method\": \"Crystal structure determination, mass spectrometry, in vitro methylation assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of substrate complex with mass spectrometry validation\",\n      \"pmids\": [\"32969463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In archaea (Haloferax volcanii), Trm112 orthologs interact with and activate multiple methyltransferases targeting translation machinery components, extending the Trm112 methyltransferase activation network beyond eukaryotes to include archaeal partners, some orthologous to eukaryotic partners and others similar to bacterial methyltransferases.\",\n      \"method\": \"Functional and structural characterization, interaction network mapping, native mass spectrometry\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods but in archaeal model system\",\n      \"pmids\": [\"30010922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human TRMT112 interacts with seven methyltransferases (N6AMT1, WBSCR22, METTL5, ALKBH8, THUMPD2, THUMPD3, TRMT11) identified by SILAC screen; TRMT112 stabilizes all seven MTases in cells; a strong mutual feedback loop exists between TRMT112 and its MTase partners; single amino acid mutations on TRMT112 surface reveal differential interaction requirements.\",\n      \"method\": \"SILAC co-immunoprecipitation, co-expression stability assays, site-directed mutagenesis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — SILAC-MS interactome with mutagenesis and stability assays across all partners\",\n      \"pmids\": [\"34948388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The METTL5-TRMT112 complex installs the m6A modification at position 1832 of human 18S rRNA; TRMT112 is required for METTL5 stability; METTL5 mutations associated with microcephaly/intellectual disability disrupt the METTL5-TRMT112 interaction; loss of METTL5 regulates gene expression at the translational level.\",\n      \"method\": \"Methyltransferase activity assays, co-immunoprecipitation, rRNA modification mapping, polysome profiling, mouse knockout studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic assays plus KO mouse model and multiple orthogonal approaches\",\n      \"pmids\": [\"35033535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BUD23-TRMT112 complex mediates chromosomal tethering of Borna disease virus 1 (BoDV-1) viral ribonucleoproteins (vRNPs); TRMT112 binds BoDV-1 L protein at the RNA-dependent RNA polymerase domain together with BUD23; the MTase activity of BUD23-TRMT112 is necessary for this chromosomal tethering.\",\n      \"method\": \"Proximity-dependent biotinylation, co-immunoprecipitation, chromosomal tethering assays, catalytic mutant analysis\",\n      \"journal\": \"Microbiology and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling plus functional tethering assays with mechanistic follow-up\",\n      \"pmids\": [\"34324219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRMT112 regulates the expression of N6AMT1 isoforms: only isoform 1 (with intact substrate binding motif) can interact with TRMT112; the alternatively spliced isoform 2 (lacking substrate binding motif) cannot interact with TRMT112 and is rapidly degraded, establishing TRMT112 as part of a cellular quality control mechanism.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assays, siRNA knockdown, isoform expression analysis\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP and stability assays\",\n      \"pmids\": [\"31466382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Covalent stereoprobes react selectively with C100 of TRMT112 only when TRMT112 is complexed with METTL5 (not other MT partners); a co-crystal structure reveals stereoprobe binding to a composite pocket templated by METTL5 and absent in other TRMT112:MT complexes; stereoprobe binding causes allosteric agonism of METTL5, demonstrating that TRMT112's C100 is part of a partner-specific composite binding site.\",\n      \"method\": \"Chemical proteomics, co-crystal structure determination, covalent probe reactivity assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus chemical proteomics and functional agonism assay\",\n      \"pmids\": [\"41507545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In yeast, the Trm11-Trm112 complex requires the CCA terminus of mature tRNA, a G10-C25 base pair, a regular-size variable region, and specific anticodon loop features for m2G10 methylation; precursor tRNA is not a substrate.\",\n      \"method\": \"In vitro methylation assays with 60 tRNA transcript variants, purification of tRNA from wild-type and deletion strains\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — systematic in vitro substrate specificity determination with in vivo validation\",\n      \"pmids\": [\"35409407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"THUMPD3-TRMT112 complex promotes TFEB translation via m2G modification of tRNALeu(CAG); deficiency of THUMPD3/TRMT112 suppresses TFEB translation, reduces autophagic flux, and inhibits pancreatic cancer cell growth.\",\n      \"method\": \"Knockdown experiments, polysome profiling, in vivo xenograft, autophagic flux assays, mechanistic tRNA modification analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic link between tRNA modification and specific translational target with in vivo validation\",\n      \"pmids\": [\"41530782\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRMT112 is a small, evolutionarily conserved 'hub' protein that functions as an obligate activating co-factor for at least seven methyltransferases (METTL5, WBSCR22/BUD23, N6AMT1/HEMK2, TRMT11, THUMPD3, THUMPD2, ALKBH8) by forming stable heterodimeric complexes through a conserved β-zipper/hydrophobic interface, stabilizing each partner against proteasomal degradation and, in several cases, directly contributing to substrate (SAM, RNA, or protein) binding; through these complexes TRMT112 orchestrates methylation of 18S rRNA (m6A via METTL5, m7G via WBSCR22), tRNAs (m2G6/7 via THUMPD3, m2G10 via TRMT11, mcm5U via ALKBH8/Trm9 in yeast), and protein translation factors (Gln185 methylation of eRF1 via N6AMT1/Mtq2), thereby coordinating the maturation of all major components of the translation apparatus.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRMT112 is an evolutionarily conserved obligate co-factor that activates at least seven methyltransferases—METTL5, WBSCR22/BUD23, N6AMT1/HEMK2, TRMT11, THUMPD3, THUMPD2, and ALKBH8—by forming stable heterodimeric complexes through a conserved β-zipper/hydrophobic interface, thereby coordinating methylation of rRNA, tRNA, and translation termination factors [PMID:21478168, PMID:26438534, PMID:34948388]. TRMT112 stabilizes each partner against ubiquitin–proteasome-dependent degradation, and in several complexes it directly contributes to SAM cofactor or RNA substrate binding; different methyltransferase partners compete for a shared interaction surface on TRMT112 [PMID:27986851, PMID:26214185, PMID:31328227]. Through these partnerships, TRMT112 controls 18S rRNA m6A (via METTL5) and m7G (via WBSCR22) modifications required for ribosome biogenesis, tRNA m2G modifications at positions 6/7 (via THUMPD3) and 10 (via TRMT11) that promote translational fidelity and efficiency, and glutamine methylation of eRF1 (via N6AMT1) needed for translation termination [PMID:35033535, PMID:34669960, PMID:31636962, PMID:25489090]. Loss of THUMPD3–TRMT112-dependent tRNA modification suppresses TFEB translation and autophagic flux, linking TRMT112's methyltransferase-activating function to downstream cellular programs including autophagy and cell growth [PMID:41530782].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Determining how TRMT112 activates structurally diverse methyltransferases, the crystal structure of yeast Mtq2–Trm112 established that TRMT112 uses a single conserved binding mode to activate partners with less than 20% sequence identity, directly enabling Gln methylation of translation termination factor eRF1.\",\n      \"evidence\": \"Crystal structure of Mtq2–Trm112 with site-directed mutagenesis and in vivo functional assays in yeast\",\n      \"pmids\": [\"21478168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for how TRMT112 discriminates among multiple partners\", \"Mammalian Mtq2/N6AMT1 complex not yet structurally resolved at this point\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing TRMT112 as essential for ribosome biogenesis, loss of Trm112 in yeast abolished Bud23-mediated 18S rRNA m7G1575 modification, destabilized Bud23 protein, prevented its recruitment to pre-ribosomes, and triggered nucleolar surveillance-mediated preribosome degradation, revealing TRMT112 as a stabilizer and recruitment factor for its partners.\",\n      \"evidence\": \"In vitro binding, in vivo stability assays, co-purification with pre-rRNAs, and methylation assays in S. cerevisiae deletion strains\",\n      \"pmids\": [\"22493060\", \"22956767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRMT112 has partners outside the methyltransferase family\", \"How TRMT112 partitions among competing partners in vivo\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolving the atomic architecture of the rRNA methyltransferase complex, crystal structures of Bud23–Trm112 in apo and SAM-bound states revealed the β-zipper interface mechanism and showed Trm112 undergoes induced fit upon partner binding, explaining its structural plasticity.\",\n      \"evidence\": \"Crystal structures (apo and SAM-bound), mutagenesis, sucrose gradient sedimentation, and co-IP in yeast\",\n      \"pmids\": [\"25489090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the induced-fit mechanism generalizes to all TRMT112 partners\", \"No structure of TRMT112 bound to an RNA substrate\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extending the mechanism to human cells, TRMT112 was shown to determine the nuclear localization and protein stability of WBSCR22, which is ubiquitinated and degraded by the proteasome when not stabilized by TRMT112; ribosome biogenesis required WBSCR22 presence rather than catalytic activity, indicating a quality-control checkpoint function.\",\n      \"evidence\": \"SILAC-Co-IP, siRNA knockdown, subcellular fractionation, ubiquitination assays, and catalytic-dead mutant analysis in human cells; crystal structure of yeast Trm9–Trm112\",\n      \"pmids\": [\"26214185\", \"25851604\", \"26438534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRMT112 shields partners from ubiquitin ligases\", \"Identity of the E3 ligase targeting free methyltransferase partners\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Addressing how TRMT112 activates tRNA methyltransferases, HDX-MS and enzymatic assays showed that Trm112 enhances SAM cofactor binding and contributes to tRNA recognition in the Trm11–Trm112 complex, and that all Trm112-dependent methyltransferases compete for the same molecular interface.\",\n      \"evidence\": \"HDX-MS, SAM-binding assays, and enzymatic activity measurements with purified yeast complexes\",\n      \"pmids\": [\"27986851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo stoichiometry and kinetic hierarchy of partner competition\", \"Whether post-translational modifications regulate partner preference\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying TRMT112 as essential for 18S rRNA m6A modification, the METTL5–TRMT112 crystal structure revealed an RNA-binding mode distinct from other m6A writers with an adenosine extrusion mechanism; separately, the human N6AMT1–TRMT112 structure confirmed the complex is a protein glutamine methyltransferase (not a DNA methyltransferase).\",\n      \"evidence\": \"Crystal structures, co-IP, rRNA modification mapping, in vitro methyltransferase assays, and protein stability assays in human cells\",\n      \"pmids\": [\"31328227\", \"31636962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No RNA-bound co-crystal structure of METTL5–TRMT112\", \"How the complex is recruited to 18S rRNA in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining the full human TRMT112 interactome, SILAC proteomics identified seven methyltransferase partners (N6AMT1, WBSCR22, METTL5, ALKBH8, THUMPD2, THUMPD3, TRMT11), all stabilized by TRMT112 with a mutual feedback loop; THUMPD3–TRMT112 was shown to be an active tRNA m2G6/7 methyltransferase whose loss impairs global protein synthesis.\",\n      \"evidence\": \"SILAC-Co-IP, mutagenesis, co-expression stability assays, RNA-MS, in vitro enzymatic assays, knockout cell analysis\",\n      \"pmids\": [\"34948388\", \"34669960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional partners exist beyond the seven identified\", \"Structural basis of THUMPD3–TRMT112 substrate recognition\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refining substrate specificity rules, the Trm11–Trm112 complex was shown to require mature tRNA features (CCA terminus, G10–C25 base pair, regular variable region) for m2G10 modification, excluding pre-tRNAs as substrates; METTL5 mutations causing microcephaly/intellectual disability were found to disrupt the METTL5–TRMT112 interaction.\",\n      \"evidence\": \"Systematic in vitro methylation with 60 tRNA variants in yeast; METTL5 disease-mutation analysis with co-IP and rRNA modification mapping in human cells and mouse models\",\n      \"pmids\": [\"35409407\", \"35033535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRMT112 dysfunction alone causes human disease\", \"Tissue-specific consequences of individual partner loss\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating partner-specific druggability, covalent stereoprobes were found to react selectively with TRMT112 C100 only when complexed with METTL5, exploiting a composite pocket absent in other TRMT112 complexes; separately, THUMPD3–TRMT112 was linked to TFEB translational control and autophagy regulation in pancreatic cancer.\",\n      \"evidence\": \"Chemical proteomics with co-crystal structure of stereoprobe-bound METTL5–TRMT112; knockdown, polysome profiling, xenograft models for THUMPD3–TRMT112 in pancreatic cancer\",\n      \"pmids\": [\"41507545\", \"41530782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether allosteric agonism of METTL5 by stereoprobes alters cellular rRNA methylation\", \"Broader translational targets beyond TFEB controlled by THUMPD3–TRMT112\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how TRMT112 is partitioned among its seven competing partners in vivo, whether TRMT112 loss-of-function mutations directly cause human Mendelian disease, and the structural basis for TRMT112 complexes with THUMPD2, THUMPD3, and ALKBH8.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vivo quantitative model of partner competition and stoichiometry\", \"No human disease mutations mapped to TRMT112 itself\", \"No crystal structures of TRMT112 with THUMPD2, THUMPD3, or ALKBH8\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 7, 13]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [3, 6, 13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 9, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 10, 11]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [\n      \"METTL5-TRMT112\",\n      \"WBSCR22/BUD23-TRMT112\",\n      \"N6AMT1/HEMK2-TRMT112\",\n      \"THUMPD3-TRMT112\"\n    ],\n    \"partners\": [\n      \"METTL5\",\n      \"WBSCR22\",\n      \"N6AMT1\",\n      \"TRMT11\",\n      \"THUMPD3\",\n      \"THUMPD2\",\n      \"ALKBH8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}