{"gene":"POLR2L","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1995,"finding":"The human hRPB7.6 (POLR2L) subunit functionally complements a S. cerevisiae mutant (rpb10-delta1::HIS3) lacking the yeast ABC10beta subunit, demonstrating that POLR2L is the functional ortholog of yeast RPB10 and is a shared subunit of all three classes of RNA polymerase. The protein contains an invariant CX2CGXnCCR motif that forms an atypical zinc-binding domain.","method":"Interspecific complementation of yeast rpb10 deletion mutant; sequence analysis of conserved zinc-binding motif","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional complementation in yeast with multiple human subunits tested, replicated across labs and organisms","pmids":["7651387"],"is_preprint":false},{"year":1996,"finding":"The POLR2L gene encodes the 67-residue hRPB7.6 subunit (7645 Da) of human RNA polymerase, is located on chromosome 11p15, comprises two exons (116 and 227 bp) separated by a ~2.1 kb intron, and is transcribed as one major mRNA in HeLa cells. Conserved cysteine residues form an atypical zinc-binding domain shared with archaeal and vaccinia virus RNA polymerase homologs, suggesting a crucial structural function. The yeast counterpart (ABC10beta) indicates POLR2L may be shared by all three classes of human nuclear RNA polymerase.","method":"Gene cloning, chromosomal mapping, sequence analysis, and comparison with archaeal/viral homologs","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gene cloning and chromosomal localization in HeLa cells; mechanistic inference on shared subunit role from yeast work","pmids":["8786124"],"is_preprint":false},{"year":1996,"finding":"Three regions of the Rpb10 subunit (corresponding to POLR2L) are strictly conserved across all eukaryotes: heptapeptides RCFT/SCGK (residues 6–12), RYCCRRM (residues 43–49), and HVDLIEK (residues 53–59). The S. pombe Rpb10 subunit can substitute for the S. cerevisiae ABC10beta, confirming its role as a shared subunit of all three nuclear RNA polymerases.","method":"PCR cloning of S. pombe rpb10+ cDNA; genetic suppression/complementation of S. cerevisiae ABC10beta mutant; comparative sequence analysis","journal":"Bioorganicheskaia khimiia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation in yeast confirming conserved shared-subunit role; single lab","pmids":["9054344"],"is_preprint":false},{"year":2024,"finding":"Knockdown of POLR2L in HCC cell lines significantly inhibited proliferation, invasion, and migration, induced apoptosis, and caused cell cycle arrest. Propofol was found to downregulate POLR2L expression, and the regulation of HCC progression by propofol was linked to a POLR2L/TGF-β signaling pathway.","method":"siRNA knockdown in HCC cell lines; proliferation, invasion, migration, and apoptosis assays; gene expression analysis; propofol treatment","journal":"Translational cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cell-line knockdown phenotypes with pathway correlation but limited mechanistic dissection of POLR2L's direct role in TGF-β signaling","pmids":["38881942"],"is_preprint":false}],"current_model":"POLR2L (hRPB7.6/RPB10beta/RPABC5) encodes a small, highly conserved ~7.6 kDa subunit shared by all three human nuclear RNA polymerases (Pol I, II, and III), containing an atypical zinc-binding domain (CX2CGXnCCR motif) essential for polymerase structural integrity; it is functionally interchangeable with its yeast (ABC10beta) and fission yeast (Rpb10) counterparts, and its depletion in cancer cell lines impairs proliferation, invasion, and migration, with one study linking it to a TGF-β signaling axis."},"narrative":{"mechanistic_narrative":"POLR2L (hRPB7.6) encodes a small, evolutionarily invariant subunit shared by all three classes of human nuclear RNA polymerase, established by its ability to functionally complement a yeast strain lacking the orthologous ABC10beta/RPB10 subunit [PMID:7651387]. The protein carries an atypical zinc-binding domain built on the invariant CX2CGXnCCR motif, with conserved cysteine residues also found in archaeal and vaccinia virus RNA polymerase homologs, pointing to a structural role in polymerase integrity [PMID:7651387, PMID:8786124]. Three short blocks of sequence are strictly conserved across eukaryotes, and the fission yeast Rpb10 can substitute for the budding yeast counterpart, reinforcing the shared-subunit assignment [PMID:9054344]. Beyond this core structural role in transcription machinery, depletion of POLR2L in hepatocellular carcinoma cell lines impairs proliferation, invasion, and migration and triggers apoptosis and cell cycle arrest [PMID:38881942].","teleology":[{"year":1995,"claim":"Established that POLR2L is the functional human ortholog of yeast RPB10 and a subunit common to all three nuclear RNA polymerases, answering whether the small hRPB7.6 protein is a bona fide polymerase component.","evidence":"Interspecific complementation of an S. cerevisiae rpb10 deletion mutant; sequence analysis of the conserved zinc-binding motif","pmids":["7651387"],"confidence":"High","gaps":["Does not resolve the structural position of the subunit within any polymerase","Does not define whether the zinc-binding domain is catalytically or purely structurally required"]},{"year":1996,"claim":"Defined the POLR2L gene structure, chromosomal location, and protein product, and tied its conserved cysteines to an atypical zinc-binding domain also present in archaeal and viral polymerases, framing a structural function.","evidence":"Gene cloning, chromosomal mapping to 11p15, and comparative sequence analysis in HeLa cells","pmids":["8786124"],"confidence":"Medium","gaps":["Shared-subunit role inferred from yeast rather than shown biochemically in human polymerases","No direct demonstration of zinc coordination"]},{"year":1996,"claim":"Pinpointed the strictly conserved sequence blocks of Rpb10 and confirmed cross-species interchangeability, consolidating the shared-subunit model across distant eukaryotes.","evidence":"PCR cloning of S. pombe rpb10+ and complementation of an S. cerevisiae ABC10beta mutant; comparative sequence analysis","pmids":["9054344"],"confidence":"Medium","gaps":["Single-lab functional data","Does not assign function to individual conserved residues in human cells"]},{"year":2024,"claim":"Connected POLR2L expression to cancer cell behavior, addressing whether loss of this core subunit produces phenotypes relevant to tumor progression.","evidence":"siRNA knockdown in HCC cell lines with proliferation, invasion, migration, and apoptosis assays, plus propofol treatment and TGF-β pathway correlation","pmids":["38881942"],"confidence":"Low","gaps":["Phenotypes may reflect general loss of transcription rather than a specific POLR2L function","Link to TGF-β signaling is correlative without mechanistic dissection","Single lab, not independently confirmed"]},{"year":null,"claim":"How POLR2L's zinc-binding domain contributes to assembly and stability within each of the three human RNA polymerases, and whether its cancer-associated phenotypes stem from a specific signaling role versus general transcription loss, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No human structural characterization of the subunit in context","No direct mechanism linking POLR2L to TGF-β signaling"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2]}],"complexes":["RNA polymerase I","RNA polymerase II","RNA polymerase III"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62875","full_name":"DNA-directed RNA polymerases I, II, and III subunit RPABC5","aliases":["DNA-directed RNA polymerase III subunit L","RNA polymerase II 7.6 kDa subunit","RPB7.6","RPB10 homolog"],"length_aa":67,"mass_kda":7.6,"function":"DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and a small RNAs, such as 5S rRNA and tRNAs, respectively","subcellular_location":"Nucleus; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P62875/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/POLR2L","classification":"Common 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POLR2L","url":"https://www.omim.org/entry/601189"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/POLR2L"},"hgnc":{"alias_symbol":["RPB10beta","RBP10","RPABC5","RPB7.6","hRPB7.6","hsRPB10b"],"prev_symbol":[]},"alphafold":{"accession":"P62875","domains":[{"cath_id":"1.10.10.60","chopping":"1-67","consensus_level":"medium","plddt":93.6745,"start":1,"end":67}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62875","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62875-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62875-F1-predicted_aligned_error_v6.png","plddt_mean":92.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=POLR2L","jax_strain_url":"https://www.jax.org/strain/search?query=POLR2L"},"sequence":{"accession":"P62875","fasta_url":"https://rest.uniprot.org/uniprotkb/P62875.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62875/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62875"}},"corpus_meta":[{"pmid":"7651387","id":"PMC_7651387","title":"Four subunits that are shared by the three classes of RNA polymerase are functionally interchangeable between Homo sapiens and Saccharomyces cerevisiae.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7651387","citation_count":108,"is_preprint":false},{"pmid":"28800584","id":"PMC_28800584","title":"Expression of the RNA-binding protein RBP10 promotes the bloodstream-form differentiation state in Trypanosoma brucei.","date":"2017","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/28800584","citation_count":67,"is_preprint":false},{"pmid":"22296558","id":"PMC_22296558","title":"Expression of the RNA recognition motif protein RBP10 promotes a bloodstream-form transcript pattern in Trypanosoma brucei.","date":"2012","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22296558","citation_count":63,"is_preprint":false},{"pmid":"19368728","id":"PMC_19368728","title":"Reverse transcription-quantitative polymerase 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and miRNA) of cisplatin-resistant gastric cancer.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29693274","citation_count":19,"is_preprint":false},{"pmid":"28381627","id":"PMC_28381627","title":"Characterization of RBP9 and RBP10, two developmentally regulated RNA-binding proteins in Trypanosoma brucei.","date":"2017","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/28381627","citation_count":16,"is_preprint":false},{"pmid":"18264749","id":"PMC_18264749","title":"Expansion of poxvirus RNA polymerase subunits sharing homology with corresponding subunits of RNA polymerase II.","date":"2008","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/18264749","citation_count":16,"is_preprint":false},{"pmid":"33117720","id":"PMC_33117720","title":"Identification of Survival-Associated Alternative Splicing Signatures in Lung Squamous Cell Carcinoma.","date":"2020","source":"Frontiers in 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to the bloodstream form by transient expression of RBP10.","date":"2017","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/28651963","citation_count":9,"is_preprint":false},{"pmid":"36369953","id":"PMC_36369953","title":"Identification of potential key genes related to idiopathic male infertility using RNA-sequencing data: an in-silico approach.","date":"2022","source":"Human fertility (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36369953","citation_count":7,"is_preprint":false},{"pmid":"9054344","id":"PMC_9054344","title":"[Three regions of Rpb10 mini-subunit of nuclear RNA polymerases are strictly conserved in all eukaryotes].","date":"1996","source":"Bioorganicheskaia khimiia","url":"https://pubmed.ncbi.nlm.nih.gov/9054344","citation_count":7,"is_preprint":false},{"pmid":"32513341","id":"PMC_32513341","title":"Roles of the Pumilio domain protein PUF3 in Trypanosoma brucei growth and differentiation.","date":"2020","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/32513341","citation_count":4,"is_preprint":false},{"pmid":"38881942","id":"PMC_38881942","title":"Propofol regulates the progression of hepatocellular carcinoma via the POLR2L/TGF-β signaling pathway.","date":"2024","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38881942","citation_count":3,"is_preprint":false},{"pmid":"40587906","id":"PMC_40587906","title":"Proteomic profiling of parthanatos and the neuroprotective potential of sodium perborate tetrahydrate.","date":"2025","source":"Journal of inorganic biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40587906","citation_count":2,"is_preprint":false},{"pmid":"35841065","id":"PMC_35841065","title":"Gel shift experiments with fragments of the Trypanosoma brucei RNA-binding protein RBP10.","date":"2022","source":"BMC research 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The protein contains an invariant CX2CGXnCCR motif that forms an atypical zinc-binding domain.\",\n      \"method\": \"Interspecific complementation of yeast rpb10 deletion mutant; sequence analysis of conserved zinc-binding motif\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional complementation in yeast with multiple human subunits tested, replicated across labs and organisms\",\n      \"pmids\": [\"7651387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The POLR2L gene encodes the 67-residue hRPB7.6 subunit (7645 Da) of human RNA polymerase, is located on chromosome 11p15, comprises two exons (116 and 227 bp) separated by a ~2.1 kb intron, and is transcribed as one major mRNA in HeLa cells. Conserved cysteine residues form an atypical zinc-binding domain shared with archaeal and vaccinia virus RNA polymerase homologs, suggesting a crucial structural function. The yeast counterpart (ABC10beta) indicates POLR2L may be shared by all three classes of human nuclear RNA polymerase.\",\n      \"method\": \"Gene cloning, chromosomal mapping, sequence analysis, and comparison with archaeal/viral homologs\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gene cloning and chromosomal localization in HeLa cells; mechanistic inference on shared subunit role from yeast work\",\n      \"pmids\": [\"8786124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Three regions of the Rpb10 subunit (corresponding to POLR2L) are strictly conserved across all eukaryotes: heptapeptides RCFT/SCGK (residues 6–12), RYCCRRM (residues 43–49), and HVDLIEK (residues 53–59). The S. pombe Rpb10 subunit can substitute for the S. cerevisiae ABC10beta, confirming its role as a shared subunit of all three nuclear RNA polymerases.\",\n      \"method\": \"PCR cloning of S. pombe rpb10+ cDNA; genetic suppression/complementation of S. cerevisiae ABC10beta mutant; comparative sequence analysis\",\n      \"journal\": \"Bioorganicheskaia khimiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation in yeast confirming conserved shared-subunit role; single lab\",\n      \"pmids\": [\"9054344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of POLR2L in HCC cell lines significantly inhibited proliferation, invasion, and migration, induced apoptosis, and caused cell cycle arrest. Propofol was found to downregulate POLR2L expression, and the regulation of HCC progression by propofol was linked to a POLR2L/TGF-β signaling pathway.\",\n      \"method\": \"siRNA knockdown in HCC cell lines; proliferation, invasion, migration, and apoptosis assays; gene expression analysis; propofol treatment\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cell-line knockdown phenotypes with pathway correlation but limited mechanistic dissection of POLR2L's direct role in TGF-β signaling\",\n      \"pmids\": [\"38881942\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POLR2L (hRPB7.6/RPB10beta/RPABC5) encodes a small, highly conserved ~7.6 kDa subunit shared by all three human nuclear RNA polymerases (Pol I, II, and III), containing an atypical zinc-binding domain (CX2CGXnCCR motif) essential for polymerase structural integrity; it is functionally interchangeable with its yeast (ABC10beta) and fission yeast (Rpb10) counterparts, and its depletion in cancer cell lines impairs proliferation, invasion, and migration, with one study linking it to a TGF-β signaling axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"POLR2L (hRPB7.6) encodes a small, evolutionarily invariant subunit shared by all three classes of human nuclear RNA polymerase, established by its ability to functionally complement a yeast strain lacking the orthologous ABC10beta/RPB10 subunit [#0]. The protein carries an atypical zinc-binding domain built on the invariant CX2CGXnCCR motif, with conserved cysteine residues also found in archaeal and vaccinia virus RNA polymerase homologs, pointing to a structural role in polymerase integrity [#0, #1]. Three short blocks of sequence are strictly conserved across eukaryotes, and the fission yeast Rpb10 can substitute for the budding yeast counterpart, reinforcing the shared-subunit assignment [#2]. Beyond this core structural role in transcription machinery, depletion of POLR2L in hepatocellular carcinoma cell lines impairs proliferation, invasion, and migration and triggers apoptosis and cell cycle arrest [#3].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that POLR2L is the functional human ortholog of yeast RPB10 and a subunit common to all three nuclear RNA polymerases, answering whether the small hRPB7.6 protein is a bona fide polymerase component.\",\n      \"evidence\": \"Interspecific complementation of an S. cerevisiae rpb10 deletion mutant; sequence analysis of the conserved zinc-binding motif\",\n      \"pmids\": [\"7651387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the structural position of the subunit within any polymerase\", \"Does not define whether the zinc-binding domain is catalytically or purely structurally required\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined the POLR2L gene structure, chromosomal location, and protein product, and tied its conserved cysteines to an atypical zinc-binding domain also present in archaeal and viral polymerases, framing a structural function.\",\n      \"evidence\": \"Gene cloning, chromosomal mapping to 11p15, and comparative sequence analysis in HeLa cells\",\n      \"pmids\": [\"8786124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shared-subunit role inferred from yeast rather than shown biochemically in human polymerases\", \"No direct demonstration of zinc coordination\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Pinpointed the strictly conserved sequence blocks of Rpb10 and confirmed cross-species interchangeability, consolidating the shared-subunit model across distant eukaryotes.\",\n      \"evidence\": \"PCR cloning of S. pombe rpb10+ and complementation of an S. cerevisiae ABC10beta mutant; comparative sequence analysis\",\n      \"pmids\": [\"9054344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional data\", \"Does not assign function to individual conserved residues in human cells\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected POLR2L expression to cancer cell behavior, addressing whether loss of this core subunit produces phenotypes relevant to tumor progression.\",\n      \"evidence\": \"siRNA knockdown in HCC cell lines with proliferation, invasion, migration, and apoptosis assays, plus propofol treatment and TGF-\\u03b2 pathway correlation\",\n      \"pmids\": [\"38881942\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Phenotypes may reflect general loss of transcription rather than a specific POLR2L function\", \"Link to TGF-\\u03b2 signaling is correlative without mechanistic dissection\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How POLR2L's zinc-binding domain contributes to assembly and stability within each of the three human RNA polymerases, and whether its cancer-associated phenotypes stem from a specific signaling role versus general transcription loss, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No human structural characterization of the subunit in context\", \"No direct mechanism linking POLR2L to TGF-\\u03b2 signaling\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"RNA polymerase I\", \"RNA polymerase II\", \"RNA polymerase III\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}