{"gene":"POLRMT","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1997,"finding":"POLRMT (h-mtRPOL) encodes the human mitochondrial RNA polymerase, a 1230 amino acid protein localized to mitochondria with sequence homology to mitochondrial RNA polymerases from lower eukaryotes and bacteriophage RNA polymerases; it carries out mitochondrial genome transcription and provides RNA primers for replication initiation.","method":"cDNA cloning, sequence analysis, chromosomal mapping (chromosome 19p13.3)","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — original identification by cDNA cloning with sequence homology analysis; foundational study but limited to sequence/expression characterization without in vitro enzymatic validation","pmids":["9097968"],"is_preprint":false},{"year":2015,"finding":"MRPL12 (mitochondrial ribosomal protein L12) binds and stabilizes POLRMT; knockdown of MRPL12 by RNAi causes instability of POLRMT protein (but not other primary mitochondrial transcription components) and a corresponding decrease in mitochondrial transcription rates. MRPL10 knockdown selectively degrades the mature long form of MRPL12 without affecting POLRMT.","method":"RNAi knockdown, co-immunoprecipitation, mitochondrial transcription rate measurement, protein stability assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional data with RNAi and transcription rate measurement, single lab, multiple orthogonal methods","pmids":["26586915"],"is_preprint":false},{"year":2017,"finding":"POLRMT has high transcriptional fidelity (average error rate ~2×10⁻⁵), with a distinctly high propensity for GTP misincorporation opposite dT (~10⁻⁴). POLRMT also shows a high mutagenic bypass rate on 8-oxo-dG templates (~10⁻⁴ C→A error rate). TEFM increases the lifetime of POLRMT on terminally mismatched elongation substrates, allowing efficient bypass of errors and continuation of transcription.","method":"In vitro transcription fidelity assay measuring catalytic efficiencies of correct and incorrect nucleotide incorporation; kinetic analysis with and without TEFM","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro reconstitution with quantitative kinetic measurements of all possible misincorporations, single lab but comprehensive and internally consistent","pmids":["28882896"],"is_preprint":false},{"year":2016,"finding":"The G-quadruplex formed between nascent RNA and non-template DNA at conserved sequence block 2 (CSB2) of human mtDNA causes transcription termination by POLRMT in vitro; longer G-tracts at CSB2 correlate with increased termination. TEFM addition prevents termination at CSB2, acting as a rheostat for POLRMT activity at this site.","method":"In vitro transcription assay with CSB2 length variants, transcript 3'-end mapping, TEFM addition experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with systematic length variants and endpoint mapping, single lab with multiple orthogonal approaches","pmids":["27436287"],"is_preprint":false},{"year":2018,"finding":"TEFM enhances POLRMT transcription elongation by increasing stall force, reducing the frequency of long-lived pauses, and shortening pause durations, without changing pause-free elongation rate. POLRMT pausing dynamics at CSB2 are directly modulated by TEFM.","method":"Single-molecule optical tweezers transcription assay measuring real-time transcription dynamics, pause frequency, and pause duration with and without TEFM","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule reconstitution with quantitative separation of pause-free elongation from pauses, rigorous mechanistic dissection in single lab","pmids":["30514634"],"is_preprint":false},{"year":2021,"finding":"Recessive and dominant variants in POLRMT cause defective mitochondrial mRNA synthesis in patient fibroblasts without mtDNA deletions or copy number changes; in vitro characterization of recombinant POLRMT mutants confirms variable but deleterious effects on mitochondrial transcription, establishing defective transcription as a disease mechanism.","method":"Patient fibroblast analysis, massive parallel sequencing, in vitro transcription assays with recombinant mutant POLRMT proteins","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — combination of in vivo patient data and in vitro biochemical reconstitution with multiple mutants, multiple families, replicated across methods","pmids":["33602924"],"is_preprint":false},{"year":2021,"finding":"Knockout of POLRMT or TFB2M in human cybrid cells results in complete mtDNA loss, demonstrating that POLRMT is indispensable for maintenance of human mtDNA (required for priming of both strand-asynchronous and strand-coupled replication).","method":"CRISPR/Cas9 knockout of POLRMT and TFB2M in human cybrid cells, 2D agarose gel electrophoresis of replication intermediates, mtDNA quantification","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined molecular phenotype (mtDNA loss), genetic complementation approach, single lab but definitive loss-of-function result","pmids":["34744028"],"is_preprint":false},{"year":2024,"finding":"POLRMT is succinylated at lysine 622; this succinylation disrupts POLRMT interaction with mtDNA and mitochondrial transcription factors. SUCLG1 restricts succinyl-CoA levels to suppress POLRMT succinylation, thereby maintaining mtDNA transcription and mitochondrial biogenesis.","method":"Mass spectrometry identification of succinylation site, site-directed mutagenesis (K622), co-immunoprecipitation of POLRMT with mtDNA/transcription factors, SUCLG1 knockdown/overexpression, succinyl-CoA measurement, mouse and humanized leukemia models","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-specific PTM identified by MS, functional validation by mutagenesis and interaction assays, multiple orthogonal methods in single lab","pmids":["38649537"],"is_preprint":false},{"year":2025,"finding":"POLRMT overexpression in mice increases mtDNA transcription initiation (elevated 7S RNA) but does not increase steady-state levels of mature mitochondrial mRNAs, indicating that post-transcriptional regulatory steps downstream of transcription initiation limit OXPHOS biogenesis. Simultaneous overexpression of POLRMT and LRPPRC also failed to increase mitochondrial transcript steady-state levels.","method":"Transgenic mouse overexpression model, RNA quantification (steady-state mRNA levels, 7S RNA), double overexpression with LRPPRC, exercise performance testing","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with multiple RNA measurements and double transgenic controls, single lab","pmids":["41107062"],"is_preprint":false},{"year":2025,"finding":"Nucleic acid sequence determinants of POLRMT transcriptional pausing were identified: a consensus pause motif 5'-R₋₁₀NNNNNNNGT₋₁G₊₁-3' (where -1 is the 3' nascent RNA nucleotide and +1 is the incoming NTP) causes strong pausing; multiple pause sites were mapped on human mtDNA. Most pause elements are shared with multisubunit prokaryotic and nuclear RNAPs despite structural differences.","method":"In vitro reconstitution of POLRMT transcription on nucleic acid scaffolds, systematic mutational analysis of pause sequences, mapping of pause sites on human mtDNA","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with systematic mutagenesis defining consensus pause motif, single lab with comprehensive mutational coverage","pmids":["40958658"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of POLRMT transcription initiation complexes (IC3 and slipped-IC3) reveal: promoter melting begins at position −4 via base-specific interactions of −4 and −3 template guanines with POLRMT and −1 non-template adenine with TFB2M; de novo RNA synthesis begins at +1; RNA slippage occurs when synthesized 2-mer RNA shifts to −1; a non-template stabilizing loop (K153LDPRSGGVIKPP165) and Y209 from TFB2M and W1026 of POLRMT recognize the conserved non-template sequence (-1)AAA(+2).","method":"Cryo-EM structure determination of active initiation complexes; structural analysis of transcription bubble, start site selection, and slippage mechanism","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures with fully resolved transcription bubbles and RNA transcripts, mechanistic interpretation directly supported by structural data","pmids":["bio_10.1101_2024.12.02.626445"],"is_preprint":true},{"year":2025,"finding":"Cryo-EM structures capturing POLRMT transitioning from open promoter complex to processive elongation complex reveal: TFAM-induced promoter bending creates a transcription-stimulatory interface between POLRMT and the upstream promoter region (UPR); UPR truncation reduces transcription from all mtDNA promoters, abolished by mutation of the POLRMT interface; the POLRMT tether helix mediates an autoinhibitory interaction with linear upstream DNA that enhances promoter specificity; deletion of the tether helix increases off-target transcription.","method":"Cryo-EM structural determination of multiple initiation complex conformations; mutational analysis of POLRMT-UPR interface and tether helix; in vitro transcription assays with truncated promoter templates","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures combined with in vitro mutagenesis and transcription assays, multiple orthogonal methods establishing mechanism","pmids":["bio_10.1101_2025.04.03.647028"],"is_preprint":true},{"year":2025,"finding":"MD simulations indicate POLRMT translocation during elongation is coupled with NTP binding to enable fingers subdomain opening post-translocation; without NTP-coupled fingers opening, translocations proceed futilely. The coupled translocation time scale exceeds hundreds of microseconds, consistent with a postcatalytic kinetic step. This suggests a variation of Brownian ratcheting in POLRMT translocation distinct from bacteriophage T7 RNAP.","method":"All-atom molecular dynamics simulation of POLRMT elongation complexes, tICA and VAMPnet dimensional reduction analyses, comparison of pre- and post-translocation models","journal":"Journal of chemical theory and computation","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulation only, no experimental validation of the proposed mechanism","pmids":["40238747"],"is_preprint":false},{"year":2005,"finding":"An alternative transcript of POLRMT containing 225 bp of intron 1 encodes a truncated protein lacking the mitochondrial targeting signal that localizes exclusively to the nucleus, proposed to correspond to nuclear RNA polymerase IV.","method":"RT-PCR detection of alternative transcripts in HeLa, mouse, and rat cells; sequence analysis of alternative exons; cellular localization inference from absence of mitochondrial targeting signal","journal":"Molekuliarnaia biologiia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RT-PCR identification of alternative transcript, nuclear localization inferred from sequence rather than direct imaging, single lab, limited functional validation","pmids":["15773549"],"is_preprint":false}],"current_model":"POLRMT is the sole mitochondrial RNA polymerase, structurally related to single-subunit phage RNAPs (e.g., T7), that assembles with TFAM and TFB2M at defined mtDNA promoters to initiate transcription through a mechanism involving TFAM-induced promoter bending, base-specific contacts for bubble melting, and start-site selection at +1; during elongation it is regulated by TEFM (which suppresses pausing and enables bypass of G-quadruplex termination signals at CSB2), by MRPL12 (which stabilizes POLRMT and activates transcription), and by succinylation at K622 (which disrupts mtDNA and transcription factor interactions and is suppressed by SUCLG1); POLRMT activity is also required for priming mtDNA replication, and its loss causes complete mtDNA depletion, while overexpression increases transcription initiation without proportionally increasing mature mRNA levels due to downstream post-transcriptional regulation."},"narrative":{"mechanistic_narrative":"POLRMT is the human mitochondrial RNA polymerase, a single-subunit enzyme homologous to bacteriophage RNA polymerases that carries out transcription of the mitochondrial genome and provides the RNA primers required to initiate mtDNA replication [PMID:9097968]. Transcription initiation requires assembly of POLRMT with accessory factors at mtDNA promoters: TFAM-induced promoter bending creates a stimulatory interface between POLRMT and the upstream promoter region, while a POLRMT tether helix autoinhibits engagement of linear upstream DNA to enforce promoter specificity [PMID:bio_10.1101_2025.04.03.647028]; promoter melting then begins around position -4 through base-specific contacts of template guanines with POLRMT and a non-template adenine with TFB2M, after which de novo synthesis starts at +1 and can undergo RNA slippage [PMID:bio_10.1101_2024.12.02.626445]. During elongation POLRMT transcribes with high fidelity (~2x10^-5 error rate) but pauses at defined nucleic-acid sequence motifs and is terminated by a G-quadruplex formed at conserved sequence block 2 (CSB2); the elongation factor TEFM acts as a rheostat that suppresses pausing, raises stall force, permits error and 8-oxo-dG bypass, and overrides CSB2 termination [PMID:28882896, PMID:27436287, PMID:30514634, PMID:40958658]. POLRMT is indispensable for mtDNA maintenance—its loss causes complete mtDNA depletion—and pathogenic POLRMT variants cause defective mitochondrial mRNA synthesis as a human disease mechanism [PMID:33602924, PMID:34744028]. Its activity is further controlled post-translationally: succinylation at K622 disrupts binding to mtDNA and transcription factors and is restrained by SUCLG1-dependent limitation of succinyl-CoA, and POLRMT protein stability and transcriptional output depend on MRPL12 [PMID:26586915, PMID:38649537]. Elevating POLRMT raises transcription initiation but not mature mRNA levels, indicating that downstream post-transcriptional steps, not initiation, limit OXPHOS biogenesis [PMID:41107062].","teleology":[{"year":1997,"claim":"Established the molecular identity of the human mitochondrial RNA polymerase, resolving which gene product transcribes the mitochondrial genome and supplies replication primers.","evidence":"cDNA cloning, sequence homology analysis, and chromosomal mapping","pmids":["9097968"],"confidence":"Medium","gaps":["No in vitro enzymatic validation in this study","Promoter recognition and factor requirements not yet defined"]},{"year":2005,"claim":"Raised the question of whether POLRMT has a non-mitochondrial role by reporting an intron-1-retaining transcript predicted to yield a nucleus-localized truncated protein.","evidence":"RT-PCR detection of alternative transcripts with localization inferred from absent mitochondrial targeting signal","pmids":["15773549"],"confidence":"Low","gaps":["Nuclear localization inferred from sequence, not imaged directly","No functional validation of a nuclear polymerase role","Not independently confirmed"]},{"year":2015,"claim":"Identified MRPL12 as a stabilizing partner of POLRMT, linking polymerase protein levels to transcriptional output.","evidence":"RNAi knockdown, co-immunoprecipitation, and mitochondrial transcription rate and protein stability assays","pmids":["26586915"],"confidence":"Medium","gaps":["Structural basis of the MRPL12-POLRMT interaction not defined","Whether MRPL12 acts at initiation or elongation unresolved"]},{"year":2016,"claim":"Defined a sequence-encoded termination mechanism by showing the CSB2 G-quadruplex terminates POLRMT and that TEFM overrides it.","evidence":"In vitro transcription with CSB2 length variants, 3'-end mapping, and TEFM addition","pmids":["27436287"],"confidence":"High","gaps":["How termination at CSB2 is coupled to replication priming in cells not directly tested"]},{"year":2017,"claim":"Quantified POLRMT transcriptional fidelity and error/damage bypass, and showed TEFM extends polymerase lifetime on mismatched substrates.","evidence":"In vitro transcription fidelity kinetics with and without TEFM, including 8-oxo-dG templates","pmids":["28882896"],"confidence":"High","gaps":["In vivo consequences of misincorporation-driven bypass not established","No proofreading mechanism characterized"]},{"year":2018,"claim":"Resolved how TEFM enhances elongation by separating pause-free rate from pausing dynamics at single-molecule resolution.","evidence":"Single-molecule optical tweezers transcription assay measuring stall force, pause frequency, and duration","pmids":["30514634"],"confidence":"High","gaps":["Structural basis of TEFM-modulated pausing not resolved here"]},{"year":2021,"claim":"Demonstrated POLRMT is essential for mtDNA maintenance and that human pathogenic variants act through defective transcription, establishing disease relevance.","evidence":"CRISPR knockout in cybrids with mtDNA quantification, and patient fibroblast analysis with recombinant mutant in vitro transcription","pmids":["34744028","33602924"],"confidence":"High","gaps":["Genotype-phenotype relationships across variants not fully mapped","Relative contribution of transcription vs replication priming defects to disease unresolved"]},{"year":2024,"claim":"Identified succinylation at K622 as a metabolic post-translational switch that inhibits POLRMT-mtDNA/factor binding and is countered by SUCLG1.","evidence":"Mass spectrometry, K622 mutagenesis, co-IP, SUCLG1 manipulation and succinyl-CoA measurement in mouse and leukemia models","pmids":["38649537"],"confidence":"High","gaps":["Enzyme catalyzing K622 succinylation not identified","Stoichiometry of succinylation in normal physiology unclear"]},{"year":2025,"claim":"Provided structural and sequence-level mechanisms for initiation and pausing: promoter bending/UPR engagement, tether-helix autoinhibition, the melting/start-site/slippage chemistry, and a consensus pause motif.","evidence":"Cryo-EM of initiation and open-to-elongation complexes with mutagenesis (preprints), plus in vitro reconstitution defining a pause consensus motif","pmids":["bio_10.1101_2024.12.02.626445","bio_10.1101_2025.04.03.647028","40958658"],"confidence":"High","gaps":["Initiation/elongation structures from preprints await peer review","How pausing is regulated in vivo and integrated with TEFM not fully resolved"]},{"year":2025,"claim":"Showed that raising POLRMT increases initiation but not mature transcript levels, locating the rate-limiting step downstream of initiation.","evidence":"Transgenic mouse POLRMT (and POLRMT+LRPPRC) overexpression with 7S RNA and steady-state mRNA quantification","pmids":["41107062"],"confidence":"Medium","gaps":["The specific post-transcriptional bottleneck not identified","Generality beyond the mouse model untested"]},{"year":null,"claim":"The molecular identity of the post-transcriptional steps that limit mature mtRNA accumulation, and the enzymes regulating POLRMT succinylation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined factor accounting for the initiation-to-mature-mRNA discrepancy","Succinyltransferase acting on K622 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,3,9,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10,11]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,5,10,11]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,4,9]}],"complexes":["mitochondrial transcription initiation complex (POLRMT-TFAM-TFB2M)"],"partners":["TFAM","TFB2M","TEFM","MRPL12","SUCLG1","LRPPRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00411","full_name":"DNA-directed RNA polymerase, mitochondrial","aliases":[],"length_aa":1230,"mass_kda":138.6,"function":"DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates (PubMed:21278163, PubMed:33602924). Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT that is required for basal transcription of mitochondrial DNA (PubMed:29149603). In this complex, TFAM recruits POLRMT to a specific promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand (PubMed:29149603). Has DNA primase activity (PubMed:18685103, PubMed:33602924). Catalyzes the synthesis of short RNA primers that are necessary for the initiation of lagging-strand DNA synthesis from the origin of light-strand DNA replication (OriL) (PubMed:18685103, PubMed:33602924)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/O00411/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/POLRMT","classification":"Common Essential","n_dependent_lines":766,"n_total_lines":1208,"dependency_fraction":0.6341059602649006},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDB1","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/POLRMT","total_profiled":1310},"omim":[{"mim_id":"620451","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 58; COXPD58","url":"https://www.omim.org/entry/620451"},{"mim_id":"619743","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 55; COXPD55","url":"https://www.omim.org/entry/619743"},{"mim_id":"618583","title":"MITOCHONDRIAL TRANSCRIPTION RESCUE FACTOR 1; MTRES1","url":"https://www.omim.org/entry/618583"},{"mim_id":"616423","title":"DExH-BOX HELICASE 30; DHX30","url":"https://www.omim.org/entry/616423"},{"mim_id":"616422","title":"TRANSCRIPTION ELONGATION FACTOR, MITOCHONDRIAL; TEFM","url":"https://www.omim.org/entry/616422"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/POLRMT"},"hgnc":{"alias_symbol":["h-mtRPOL","APOLMT","MTRNAP","MTRPOL"],"prev_symbol":[]},"alphafold":{"accession":"O00411","domains":[{"cath_id":"1.25.40","chopping":"170-178_188-193_220-355","consensus_level":"high","plddt":89.4114,"start":170,"end":355},{"cath_id":"-","chopping":"394-415_429-589_629-668","consensus_level":"high","plddt":92.8664,"start":394,"end":668},{"cath_id":"1.10.287.280","chopping":"710-918","consensus_level":"medium","plddt":94.5046,"start":710,"end":918},{"cath_id":"-","chopping":"919-938_1051-1103_1112-1230","consensus_level":"medium","plddt":91.9432,"start":919,"end":1230},{"cath_id":"-","chopping":"955-1044","consensus_level":"medium","plddt":91.7121,"start":955,"end":1044}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00411","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00411-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00411-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=POLRMT","jax_strain_url":"https://www.jax.org/strain/search?query=POLRMT"},"sequence":{"accession":"O00411","fasta_url":"https://rest.uniprot.org/uniprotkb/O00411.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00411/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00411"}},"corpus_meta":[{"pmid":"9097968","id":"PMC_9097968","title":"Identification of the gene encoding the human mitochondrial RNA polymerase (h-mtRPOL) by cyberscreening of the Expressed Sequence Tags database.","date":"1997","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9097968","citation_count":147,"is_preprint":false},{"pmid":"33602924","id":"PMC_33602924","title":"POLRMT mutations impair mitochondrial transcription causing neurological disease.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33602924","citation_count":54,"is_preprint":false},{"pmid":"26586915","id":"PMC_26586915","title":"Mitochondrial Ribosomal Protein L12 Is Required for POLRMT Stability and Exists as Two Forms Generated by Alternative Proteolysis during Import.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26586915","citation_count":43,"is_preprint":false},{"pmid":"28882896","id":"PMC_28882896","title":"Transcriptional fidelities of human mitochondrial POLRMT, yeast mitochondrial Rpo41, and phage T7 single-subunit RNA polymerases.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28882896","citation_count":34,"is_preprint":false},{"pmid":"38649537","id":"PMC_38649537","title":"SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/38649537","citation_count":30,"is_preprint":false},{"pmid":"27436287","id":"PMC_27436287","title":"Length heterogeneity at conserved sequence block 2 in human mitochondrial DNA acts as a rheostat for RNA polymerase POLRMT activity.","date":"2016","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27436287","citation_count":27,"is_preprint":false},{"pmid":"36823110","id":"PMC_36823110","title":"A first-in-class POLRMT specific inhibitor IMT1 suppresses endometrial carcinoma cell growth.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36823110","citation_count":26,"is_preprint":false},{"pmid":"34744028","id":"PMC_34744028","title":"TFB2M and POLRMT are essential for mammalian mitochondrial DNA replication.","date":"2021","source":"Biochimica et biophysica acta. 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of 6-Fluorine-Substituted Coumarin Analogues as POLRMT Inhibitors with High Potency and Safety for Treatment of Pancreatic Cancer.","date":"2024","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39049433","citation_count":3,"is_preprint":false},{"pmid":"40706667","id":"PMC_40706667","title":"POLRMT enhances lenvatinib resistance in hepatocellular carcinoma cells by maintaining mitochondrial ATP production.","date":"2025","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40706667","citation_count":2,"is_preprint":false},{"pmid":"15773549","id":"PMC_15773549","title":"[Alternative transcripts from POLRMT responsible for synthesis of nuclear RNA polymerase IV].","date":"2005","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/15773549","citation_count":2,"is_preprint":false},{"pmid":"40238747","id":"PMC_40238747","title":"Collective Variables and Facilitated Conformational Opening during Translocation of Human 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initiation.\",\n      \"method\": \"cDNA cloning, sequence analysis, chromosomal mapping (chromosome 19p13.3)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — original identification by cDNA cloning with sequence homology analysis; foundational study but limited to sequence/expression characterization without in vitro enzymatic validation\",\n      \"pmids\": [\"9097968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MRPL12 (mitochondrial ribosomal protein L12) binds and stabilizes POLRMT; knockdown of MRPL12 by RNAi causes instability of POLRMT protein (but not other primary mitochondrial transcription components) and a corresponding decrease in mitochondrial transcription rates. MRPL10 knockdown selectively degrades the mature long form of MRPL12 without affecting POLRMT.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, mitochondrial transcription rate measurement, protein stability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional data with RNAi and transcription rate measurement, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26586915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"POLRMT has high transcriptional fidelity (average error rate ~2×10⁻⁵), with a distinctly high propensity for GTP misincorporation opposite dT (~10⁻⁴). POLRMT also shows a high mutagenic bypass rate on 8-oxo-dG templates (~10⁻⁴ C→A error rate). TEFM increases the lifetime of POLRMT on terminally mismatched elongation substrates, allowing efficient bypass of errors and continuation of transcription.\",\n      \"method\": \"In vitro transcription fidelity assay measuring catalytic efficiencies of correct and incorrect nucleotide incorporation; kinetic analysis with and without TEFM\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro reconstitution with quantitative kinetic measurements of all possible misincorporations, single lab but comprehensive and internally consistent\",\n      \"pmids\": [\"28882896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The G-quadruplex formed between nascent RNA and non-template DNA at conserved sequence block 2 (CSB2) of human mtDNA causes transcription termination by POLRMT in vitro; longer G-tracts at CSB2 correlate with increased termination. TEFM addition prevents termination at CSB2, acting as a rheostat for POLRMT activity at this site.\",\n      \"method\": \"In vitro transcription assay with CSB2 length variants, transcript 3'-end mapping, TEFM addition experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with systematic length variants and endpoint mapping, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"27436287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TEFM enhances POLRMT transcription elongation by increasing stall force, reducing the frequency of long-lived pauses, and shortening pause durations, without changing pause-free elongation rate. POLRMT pausing dynamics at CSB2 are directly modulated by TEFM.\",\n      \"method\": \"Single-molecule optical tweezers transcription assay measuring real-time transcription dynamics, pause frequency, and pause duration with and without TEFM\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule reconstitution with quantitative separation of pause-free elongation from pauses, rigorous mechanistic dissection in single lab\",\n      \"pmids\": [\"30514634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Recessive and dominant variants in POLRMT cause defective mitochondrial mRNA synthesis in patient fibroblasts without mtDNA deletions or copy number changes; in vitro characterization of recombinant POLRMT mutants confirms variable but deleterious effects on mitochondrial transcription, establishing defective transcription as a disease mechanism.\",\n      \"method\": \"Patient fibroblast analysis, massive parallel sequencing, in vitro transcription assays with recombinant mutant POLRMT proteins\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — combination of in vivo patient data and in vitro biochemical reconstitution with multiple mutants, multiple families, replicated across methods\",\n      \"pmids\": [\"33602924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockout of POLRMT or TFB2M in human cybrid cells results in complete mtDNA loss, demonstrating that POLRMT is indispensable for maintenance of human mtDNA (required for priming of both strand-asynchronous and strand-coupled replication).\",\n      \"method\": \"CRISPR/Cas9 knockout of POLRMT and TFB2M in human cybrid cells, 2D agarose gel electrophoresis of replication intermediates, mtDNA quantification\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined molecular phenotype (mtDNA loss), genetic complementation approach, single lab but definitive loss-of-function result\",\n      \"pmids\": [\"34744028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"POLRMT is succinylated at lysine 622; this succinylation disrupts POLRMT interaction with mtDNA and mitochondrial transcription factors. SUCLG1 restricts succinyl-CoA levels to suppress POLRMT succinylation, thereby maintaining mtDNA transcription and mitochondrial biogenesis.\",\n      \"method\": \"Mass spectrometry identification of succinylation site, site-directed mutagenesis (K622), co-immunoprecipitation of POLRMT with mtDNA/transcription factors, SUCLG1 knockdown/overexpression, succinyl-CoA measurement, mouse and humanized leukemia models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-specific PTM identified by MS, functional validation by mutagenesis and interaction assays, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"38649537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"POLRMT overexpression in mice increases mtDNA transcription initiation (elevated 7S RNA) but does not increase steady-state levels of mature mitochondrial mRNAs, indicating that post-transcriptional regulatory steps downstream of transcription initiation limit OXPHOS biogenesis. Simultaneous overexpression of POLRMT and LRPPRC also failed to increase mitochondrial transcript steady-state levels.\",\n      \"method\": \"Transgenic mouse overexpression model, RNA quantification (steady-state mRNA levels, 7S RNA), double overexpression with LRPPRC, exercise performance testing\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with multiple RNA measurements and double transgenic controls, single lab\",\n      \"pmids\": [\"41107062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nucleic acid sequence determinants of POLRMT transcriptional pausing were identified: a consensus pause motif 5'-R₋₁₀NNNNNNNGT₋₁G₊₁-3' (where -1 is the 3' nascent RNA nucleotide and +1 is the incoming NTP) causes strong pausing; multiple pause sites were mapped on human mtDNA. Most pause elements are shared with multisubunit prokaryotic and nuclear RNAPs despite structural differences.\",\n      \"method\": \"In vitro reconstitution of POLRMT transcription on nucleic acid scaffolds, systematic mutational analysis of pause sequences, mapping of pause sites on human mtDNA\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with systematic mutagenesis defining consensus pause motif, single lab with comprehensive mutational coverage\",\n      \"pmids\": [\"40958658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of POLRMT transcription initiation complexes (IC3 and slipped-IC3) reveal: promoter melting begins at position −4 via base-specific interactions of −4 and −3 template guanines with POLRMT and −1 non-template adenine with TFB2M; de novo RNA synthesis begins at +1; RNA slippage occurs when synthesized 2-mer RNA shifts to −1; a non-template stabilizing loop (K153LDPRSGGVIKPP165) and Y209 from TFB2M and W1026 of POLRMT recognize the conserved non-template sequence (-1)AAA(+2).\",\n      \"method\": \"Cryo-EM structure determination of active initiation complexes; structural analysis of transcription bubble, start site selection, and slippage mechanism\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures with fully resolved transcription bubbles and RNA transcripts, mechanistic interpretation directly supported by structural data\",\n      \"pmids\": [\"bio_10.1101_2024.12.02.626445\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures capturing POLRMT transitioning from open promoter complex to processive elongation complex reveal: TFAM-induced promoter bending creates a transcription-stimulatory interface between POLRMT and the upstream promoter region (UPR); UPR truncation reduces transcription from all mtDNA promoters, abolished by mutation of the POLRMT interface; the POLRMT tether helix mediates an autoinhibitory interaction with linear upstream DNA that enhances promoter specificity; deletion of the tether helix increases off-target transcription.\",\n      \"method\": \"Cryo-EM structural determination of multiple initiation complex conformations; mutational analysis of POLRMT-UPR interface and tether helix; in vitro transcription assays with truncated promoter templates\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures combined with in vitro mutagenesis and transcription assays, multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"bio_10.1101_2025.04.03.647028\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MD simulations indicate POLRMT translocation during elongation is coupled with NTP binding to enable fingers subdomain opening post-translocation; without NTP-coupled fingers opening, translocations proceed futilely. The coupled translocation time scale exceeds hundreds of microseconds, consistent with a postcatalytic kinetic step. This suggests a variation of Brownian ratcheting in POLRMT translocation distinct from bacteriophage T7 RNAP.\",\n      \"method\": \"All-atom molecular dynamics simulation of POLRMT elongation complexes, tICA and VAMPnet dimensional reduction analyses, comparison of pre- and post-translocation models\",\n      \"journal\": \"Journal of chemical theory and computation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulation only, no experimental validation of the proposed mechanism\",\n      \"pmids\": [\"40238747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"An alternative transcript of POLRMT containing 225 bp of intron 1 encodes a truncated protein lacking the mitochondrial targeting signal that localizes exclusively to the nucleus, proposed to correspond to nuclear RNA polymerase IV.\",\n      \"method\": \"RT-PCR detection of alternative transcripts in HeLa, mouse, and rat cells; sequence analysis of alternative exons; cellular localization inference from absence of mitochondrial targeting signal\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RT-PCR identification of alternative transcript, nuclear localization inferred from sequence rather than direct imaging, single lab, limited functional validation\",\n      \"pmids\": [\"15773549\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POLRMT is the sole mitochondrial RNA polymerase, structurally related to single-subunit phage RNAPs (e.g., T7), that assembles with TFAM and TFB2M at defined mtDNA promoters to initiate transcription through a mechanism involving TFAM-induced promoter bending, base-specific contacts for bubble melting, and start-site selection at +1; during elongation it is regulated by TEFM (which suppresses pausing and enables bypass of G-quadruplex termination signals at CSB2), by MRPL12 (which stabilizes POLRMT and activates transcription), and by succinylation at K622 (which disrupts mtDNA and transcription factor interactions and is suppressed by SUCLG1); POLRMT activity is also required for priming mtDNA replication, and its loss causes complete mtDNA depletion, while overexpression increases transcription initiation without proportionally increasing mature mRNA levels due to downstream post-transcriptional regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"POLRMT is the human mitochondrial RNA polymerase, a single-subunit enzyme homologous to bacteriophage RNA polymerases that carries out transcription of the mitochondrial genome and provides the RNA primers required to initiate mtDNA replication [#0]. Transcription initiation requires assembly of POLRMT with accessory factors at mtDNA promoters: TFAM-induced promoter bending creates a stimulatory interface between POLRMT and the upstream promoter region, while a POLRMT tether helix autoinhibits engagement of linear upstream DNA to enforce promoter specificity [#11]; promoter melting then begins around position -4 through base-specific contacts of template guanines with POLRMT and a non-template adenine with TFB2M, after which de novo synthesis starts at +1 and can undergo RNA slippage [#10]. During elongation POLRMT transcribes with high fidelity (~2x10^-5 error rate) but pauses at defined nucleic-acid sequence motifs and is terminated by a G-quadruplex formed at conserved sequence block 2 (CSB2); the elongation factor TEFM acts as a rheostat that suppresses pausing, raises stall force, permits error and 8-oxo-dG bypass, and overrides CSB2 termination [#2, #3, #4, #9]. POLRMT is indispensable for mtDNA maintenance—its loss causes complete mtDNA depletion—and pathogenic POLRMT variants cause defective mitochondrial mRNA synthesis as a human disease mechanism [#5, #6]. Its activity is further controlled post-translationally: succinylation at K622 disrupts binding to mtDNA and transcription factors and is restrained by SUCLG1-dependent limitation of succinyl-CoA, and POLRMT protein stability and transcriptional output depend on MRPL12 [#1, #7]. Elevating POLRMT raises transcription initiation but not mature mRNA levels, indicating that downstream post-transcriptional steps, not initiation, limit OXPHOS biogenesis [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the molecular identity of the human mitochondrial RNA polymerase, resolving which gene product transcribes the mitochondrial genome and supplies replication primers.\",\n      \"evidence\": \"cDNA cloning, sequence homology analysis, and chromosomal mapping\",\n      \"pmids\": [\"9097968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro enzymatic validation in this study\", \"Promoter recognition and factor requirements not yet defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Raised the question of whether POLRMT has a non-mitochondrial role by reporting an intron-1-retaining transcript predicted to yield a nucleus-localized truncated protein.\",\n      \"evidence\": \"RT-PCR detection of alternative transcripts with localization inferred from absent mitochondrial targeting signal\",\n      \"pmids\": [\"15773549\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Nuclear localization inferred from sequence, not imaged directly\", \"No functional validation of a nuclear polymerase role\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified MRPL12 as a stabilizing partner of POLRMT, linking polymerase protein levels to transcriptional output.\",\n      \"evidence\": \"RNAi knockdown, co-immunoprecipitation, and mitochondrial transcription rate and protein stability assays\",\n      \"pmids\": [\"26586915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the MRPL12-POLRMT interaction not defined\", \"Whether MRPL12 acts at initiation or elongation unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a sequence-encoded termination mechanism by showing the CSB2 G-quadruplex terminates POLRMT and that TEFM overrides it.\",\n      \"evidence\": \"In vitro transcription with CSB2 length variants, 3'-end mapping, and TEFM addition\",\n      \"pmids\": [\"27436287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How termination at CSB2 is coupled to replication priming in cells not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Quantified POLRMT transcriptional fidelity and error/damage bypass, and showed TEFM extends polymerase lifetime on mismatched substrates.\",\n      \"evidence\": \"In vitro transcription fidelity kinetics with and without TEFM, including 8-oxo-dG templates\",\n      \"pmids\": [\"28882896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequences of misincorporation-driven bypass not established\", \"No proofreading mechanism characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved how TEFM enhances elongation by separating pause-free rate from pausing dynamics at single-molecule resolution.\",\n      \"evidence\": \"Single-molecule optical tweezers transcription assay measuring stall force, pause frequency, and duration\",\n      \"pmids\": [\"30514634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TEFM-modulated pausing not resolved here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated POLRMT is essential for mtDNA maintenance and that human pathogenic variants act through defective transcription, establishing disease relevance.\",\n      \"evidence\": \"CRISPR knockout in cybrids with mtDNA quantification, and patient fibroblast analysis with recombinant mutant in vitro transcription\",\n      \"pmids\": [\"34744028\", \"33602924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype relationships across variants not fully mapped\", \"Relative contribution of transcription vs replication priming defects to disease unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified succinylation at K622 as a metabolic post-translational switch that inhibits POLRMT-mtDNA/factor binding and is countered by SUCLG1.\",\n      \"evidence\": \"Mass spectrometry, K622 mutagenesis, co-IP, SUCLG1 manipulation and succinyl-CoA measurement in mouse and leukemia models\",\n      \"pmids\": [\"38649537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme catalyzing K622 succinylation not identified\", \"Stoichiometry of succinylation in normal physiology unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided structural and sequence-level mechanisms for initiation and pausing: promoter bending/UPR engagement, tether-helix autoinhibition, the melting/start-site/slippage chemistry, and a consensus pause motif.\",\n      \"evidence\": \"Cryo-EM of initiation and open-to-elongation complexes with mutagenesis (preprints), plus in vitro reconstitution defining a pause consensus motif\",\n      \"pmids\": [\"bio_10.1101_2024.12.02.626445\", \"bio_10.1101_2025.04.03.647028\", \"40958658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Initiation/elongation structures from preprints await peer review\", \"How pausing is regulated in vivo and integrated with TEFM not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that raising POLRMT increases initiation but not mature transcript levels, locating the rate-limiting step downstream of initiation.\",\n      \"evidence\": \"Transgenic mouse POLRMT (and POLRMT+LRPPRC) overexpression with 7S RNA and steady-state mRNA quantification\",\n      \"pmids\": [\"41107062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific post-transcriptional bottleneck not identified\", \"Generality beyond the mouse model untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the post-transcriptional steps that limit mature mtRNA accumulation, and the enzymes regulating POLRMT succinylation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined factor accounting for the initiation-to-mature-mRNA discrepancy\", \"Succinyltransferase acting on K622 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 3, 9, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 5, 10, 11]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 4, 9]}\n    ],\n    \"complexes\": [\"mitochondrial transcription initiation complex (POLRMT-TFAM-TFB2M)\"],\n    \"partners\": [\"TFAM\", \"TFB2M\", \"TEFM\", \"MRPL12\", \"SUCLG1\", \"LRPPRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}