{"gene":"POLR1G","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":1997,"finding":"The yeast RNA Pol I-specific subunit A34.5 (ortholog of human POLR1G/PAF49) is a phosphoprotein that copurifies with RNA Pol I and is required for stable association of subunit A49 with the enzyme; cells lacking A34.5 produce a structurally altered, catalytically active Pol I that lacks A49 upon in vitro purification. Genetic epistasis showed that A34.5 becomes quasi-essential in strains lacking DNA topoisomerase I, suggesting a specific role in helping Pol I overcome topological constraints during rDNA transcription. Synthetic lethality with A14 deletion (rescued by Pol II-driven pre-rRNA) demonstrated that A34.5 is collectively essential for rRNA synthesis.","method":"Genetic deletion analysis, in vitro purification/reconstitution of RNA Pol I, complementation by Pol II-driven pre-rRNA, double and triple mutant epistasis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal genetic and biochemical methods in a single rigorous study; reconstitution of mutant enzyme in vitro with clear phenotypic readouts","pmids":["9121426"],"is_preprint":false},{"year":2004,"finding":"Mouse PAF49 (ortholog of human POLR1G) copurifies and coimmunoprecipitates with a transcriptionally active subpopulation of RNA Pol I. PAF49 physically interacts with PAF53 through its N-terminal segment, and this same region interacts with TAF(I)48 (a subunit of SL1/selectivity factor), pulling down the entire SL1 complex. Anti-PAF49 antibody severely impairs specific rDNA transcription in vitro, an effect rescued by recombinant PAF49. Overexpression of a PAF49 deletion mutant reduces pre-rRNA synthesis in vivo. PAF49 localizes to the nucleolus in growing cells but disperses to the nucleoplasm in growth-arrested cells.","method":"Coimmunoprecipitation, in vitro transcription assay with antibody inhibition and recombinant protein rescue, immunolocalization, overexpression of dominant-negative deletion mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, in vitro transcription inhibition/rescue, dominant-negative OE, localization) in a single study with clear functional readouts","pmids":["15226435"],"is_preprint":false},{"year":2006,"finding":"Human CAST/hPAF49 (POLR1G) is a bona fide RNA Pol I-specific subunit present in initiation-competent Pol Iβ complexes in HeLa cells. It undergoes growth-regulated tyrosine phosphorylation at a conserved residue. CAST/hPAF49 interacts with the activator UBF and weakly with SL1 at the rDNA promoter. CAST/hPAF49-specific antibodies and excess CAST/hPAF49 protein inhibit UBF-activated (but not basal) Pol I transcription after SL1-Pol I-rDNA complex assembly, and disrupt the UBF–CAST/hPAF49 interaction, indicating that the interaction of this Pol I-specific subunit with UBF is required for transcriptional activation.","method":"Biochemical purification of Pol I complexes, coimmunoprecipitation, in vitro transcription inhibition assays with antibodies and recombinant protein, phosphorylation analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, in vitro transcription with antibody and excess protein inhibition, phosphorylation mapping) establishing mechanism; strong within single study","pmids":["16809778"],"is_preprint":false},{"year":2012,"finding":"Mammalian PAF49 (POLR1G) and PAF53 form a heterodimer, and deletion mutagenesis identified that amino acids 41–86 of PAF49 are sufficient for heterodimerization with PAF53. This region is structurally analogous to yeast A34.5 residues 52–98, and substituting the yeast A34.5 sequence with mammalian PAF49 residues 41–86 enabled interspecific heterodimerization with mouse PAF53, confirming conserved structural organization. The mammalian PAF49/PAF53 heterodimer is the functional equivalent of the yeast A34.5/A49 TFIIF-like subcomplex.","method":"Deletion and substitution mutagenesis of PAF49 and PAF53, coimmunoprecipitation of heterodimers, in silico structural prediction","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal deletion mutagenesis with Co-IP, single lab, supported by structural analogy to yeast system","pmids":["22849406"],"is_preprint":false},{"year":2014,"finding":"The association of the PAF49/PAF53 (POLR1G-containing) heterodimer with RNA Pol I is regulated: PAF49 is acetylated on multiple sites, and hypoacetylated PAF49/PAF53 heterodimer binds Pol I with greater affinity than acetylated heterodimer. The heterodimer also physically interacts with Rrn3, and this interaction is proposed to facilitate recruitment of Rrn3 to Pol I, linking the heterodimer to transcription initiation. Nucleolar levels of PAF49/PAF53 are regulated independently of total protein levels.","method":"Coimmunoprecipitation, acetylation analysis, subcellular fractionation/nucleolar localization, protein interaction assays","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and acetylation mapping in single lab, moderate mechanistic follow-up","pmids":["25225125"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM structures of yeast RNA Pol I elongation complexes at 3.2–3.4 Å resolution reveal that the A49–A34.5 (POLR1G ortholog) heterodimer is dissociated from most nucleotide-bound elongation complexes, which instead adopt a Pol II-like conformation. In the absence of the heterodimer, the A12.2 C-terminal domain occupies a previously unobserved position at the A135 surface. This structural and biochemical data supports a model in which reversible binding of the A49–A34.5 heterodimer regulates the transition between transcription initiation and elongation states of Pol I.","method":"Cryo-electron microscopy at 3.2–3.4 Å resolution, biochemical reconstitution of elongation complexes with nucleotide analog GMPCPP","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — near-atomic resolution cryo-EM structure with biochemical validation, revealing specific functional conformational states","pmids":["30913026"],"is_preprint":false},{"year":2009,"finding":"The histone chaperone FACT (SSRP1 and Spt16 subunits) co-purifies and co-immunoprecipitates with mammalian RNA Pol I complexes (which contain PAF49/POLR1G). siRNA-mediated depletion of FACT subunits significantly reduces 47S pre-rRNA levels without affecting synthesis of the first 40 nt of rRNA, indicating FACT is required for Pol I transcription elongation through chromatin. This places POLR1G-containing Pol I complexes in a pathway requiring FACT for chromatin template transcription.","method":"Coimmunoprecipitation of FACT with Pol I, siRNA knockdown of FACT subunits with pre-rRNA level measurement, ChIP at rDNA loci","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional siRNA knockdown with defined phenotype, single lab","pmids":["19214185"],"is_preprint":false}],"current_model":"POLR1G (human PAF49/CAST/hPAF49; yeast ortholog A34.5) is a Pol I-specific subunit that forms a TFIIF-like heterodimer with PAF53 (A49), associates with transcription-initiation-competent Pol I complexes in the nucleolus, undergoes growth-regulated tyrosine phosphorylation, interacts with the transcriptional activator UBF to stimulate rDNA transcription beyond basal levels, and whose reversible dissociation from the elongation complex (as shown by cryo-EM) is proposed to regulate the switch between Pol I initiation and elongation; acetylation of PAF49 modulates its affinity for Pol I and facilitates Rrn3 recruitment, while the A34.5 yeast ortholog helps Pol I overcome topological constraints during rDNA transcription."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that A34.5 (POLR1G ortholog) is a Pol I-specific subunit required for stable A49 association and collectively essential for rRNA synthesis answered the foundational question of whether this subunit has a dedicated role in Pol I rather than being a loosely associated factor.","evidence":"Genetic deletion, in vitro Pol I purification/reconstitution, and synthetic lethality analysis in yeast","pmids":["9121426"],"confidence":"High","gaps":["Mechanism by which A34.5 helps Pol I overcome topological constraints not determined at molecular level","Whether loss of A34.5 affects transcription initiation, elongation, or both was not resolved"]},{"year":2004,"claim":"Demonstrating that mammalian PAF49 copurifies with transcriptionally active Pol I, interacts with PAF53 and SL1, and is required for rDNA transcription established its conserved role as a functional Pol I subunit bridging the enzyme to the initiation machinery.","evidence":"Co-IP, antibody-mediated in vitro transcription inhibition with recombinant protein rescue, dominant-negative overexpression, and nucleolar immunolocalization in mouse cells","pmids":["15226435"],"confidence":"High","gaps":["Whether the PAF49–SL1 interaction is direct or mediated through TAF(I)48 exclusively was not resolved","Growth-regulated mechanism controlling PAF49 nucleolar versus nucleoplasmic redistribution unknown"]},{"year":2006,"claim":"Identifying that POLR1G undergoes growth-regulated tyrosine phosphorylation and that its interaction with UBF is specifically required for activated (not basal) Pol I transcription resolved how Pol I-specific subunits transduce activator signals during rDNA transcription.","evidence":"Biochemical purification, Co-IP, in vitro transcription assays with antibody and excess protein inhibition in HeLa cells","pmids":["16809778"],"confidence":"High","gaps":["Identity of the kinase responsible for growth-regulated tyrosine phosphorylation not determined","Functional consequence of tyrosine phosphorylation on UBF interaction or transcription not directly tested"]},{"year":2009,"claim":"The finding that the histone chaperone FACT co-purifies with POLR1G-containing Pol I and is required for Pol I elongation through chromatin placed POLR1G in a chromatin-dependent elongation pathway.","evidence":"Co-IP of FACT with Pol I and siRNA knockdown with pre-rRNA measurement in mammalian cells","pmids":["19214185"],"confidence":"Medium","gaps":["Whether POLR1G/PAF49 directly contacts FACT or is merely a co-resident in the same Pol I complex is unresolved","Effect of PAF49 depletion on FACT recruitment not tested"]},{"year":2012,"claim":"Mapping the minimal PAF49 heterodimerization domain (aa 41–86) and demonstrating interspecific heterodimerization with yeast A34.5 sequences confirmed structural conservation of the TFIIF-like architecture across eukaryotes.","evidence":"Deletion and substitution mutagenesis with Co-IP of heterodimers","pmids":["22849406"],"confidence":"Medium","gaps":["No high-resolution structure of the mammalian PAF49–PAF53 heterodimer","Functional consequence of disrupting specific residues within the dimerization domain not tested in transcription assays"]},{"year":2014,"claim":"Revealing that acetylation of PAF49 reduces its affinity for Pol I and that the PAF49/PAF53 heterodimer interacts with Rrn3 linked post-translational modification of POLR1G to regulation of Pol I initiation factor recruitment.","evidence":"Co-IP, acetylation mapping, and nucleolar fractionation in mammalian cells","pmids":["25225125"],"confidence":"Medium","gaps":["Acetyltransferase and deacetylase acting on PAF49 not identified","Whether acetylation directly regulates Rrn3 recruitment in vivo not demonstrated","Functional impact of individual acetylation sites not resolved"]},{"year":2019,"claim":"Near-atomic cryo-EM structures showing that the A49–A34.5 heterodimer dissociates from Pol I during elongation, with the enzyme adopting a Pol II-like conformation, provided the structural basis for the model that POLR1G reversibly regulates the initiation-to-elongation transition.","evidence":"Cryo-EM at 3.2–3.4 Å of yeast Pol I elongation complexes with biochemical reconstitution","pmids":["30913026"],"confidence":"High","gaps":["Dynamics of heterodimer dissociation and re-association in living cells not measured","Whether mammalian PAF49–PAF53 undergoes the same dissociation during elongation not confirmed","Signals or factors triggering heterodimer release remain unknown"]},{"year":null,"claim":"The kinase(s) responsible for growth-regulated tyrosine phosphorylation of POLR1G, the acetyltransferase/deacetylase pair controlling its acetylation state, and whether heterodimer dissociation during elongation occurs in mammalian Pol I remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of the mammalian PAF49–PAF53 heterodimer exists","In vivo dynamics of heterodimer association with Pol I during the transcription cycle are uncharacterized","How tyrosine phosphorylation and acetylation are coordinated to regulate POLR1G function is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2,5]}],"complexes":["RNA polymerase I","PAF49-PAF53 (A34.5-A49) TFIIF-like heterodimer"],"partners":["POLR1E","UBF","RRN3","TAF1A"],"other_free_text":[]},"mechanistic_narrative":"POLR1G (PAF49/CAST/A34.5) is an RNA polymerase I-specific subunit that forms a TFIIF-like heterodimer with PAF53 (A49) and is required for stable incorporation of PAF53 into the Pol I enzyme and for activated rDNA transcription [PMID:9121426, PMID:22849406]. Within initiation-competent Pol Iβ complexes in the nucleolus, POLR1G undergoes growth-regulated tyrosine phosphorylation and interacts with the transcriptional activator UBF to enable UBF-dependent (but not basal) transcription, while acetylation of POLR1G modulates its affinity for Pol I and facilitates Rrn3 recruitment [PMID:16809778, PMID:25225125]. Cryo-EM structures of yeast Pol I elongation complexes show that the A49–A34.5 heterodimer reversibly dissociates during elongation, adopting a Pol II-like conformation, supporting a model in which POLR1G regulates the switch between transcription initiation and elongation [PMID:30913026]. In yeast, the A34.5 ortholog becomes quasi-essential in strains lacking DNA topoisomerase I, indicating a role in overcoming topological constraints during rDNA transcription [PMID:9121426]."},"prefetch_data":{"uniprot":{"accession":"O15446","full_name":"DNA-directed RNA polymerase I subunit RPA34","aliases":["A34.5","Antisense to ERCC-1 protein","ASE-1","CD3-epsilon-associated protein","CD3E-associated protein","DNA-directed RNA polymerase I subunit G","RNA polymerase I-associated factor PAF49"],"length_aa":510,"mass_kda":55.0,"function":"Component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates. Involved in UBTF-activated transcription, presumably at a step following PIC formation Has been described as a component of preformed T-cell receptor (TCR) complex","subcellular_location":"Nucleus, nucleolus; Chromosome","url":"https://www.uniprot.org/uniprotkb/O15446/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/POLR1G","classification":"Common Essential","n_dependent_lines":562,"n_total_lines":1208,"dependency_fraction":0.4652317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"POLR2F","stoichiometry":10.0},{"gene":"POLR2K","stoichiometry":10.0},{"gene":"POLR1B","stoichiometry":4.0},{"gene":"POLR2E","stoichiometry":4.0},{"gene":"POLR2H","stoichiometry":4.0},{"gene":"POLR1C","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/POLR1G","total_profiled":1310},"omim":[{"mim_id":"621031","title":"POLYMERASE I, RNA, SUBUNIT E; POLR1E","url":"https://www.omim.org/entry/621031"},{"mim_id":"107325","title":"POLYMERASE I, RNA, SUBUNIT G; POLR1G","url":"https://www.omim.org/entry/107325"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nucleoli fibrillar center","reliability":"Enhanced"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/POLR1G"},"hgnc":{"alias_symbol":["ASE-1","CAST","PAF49","RPA34","A34.5"],"prev_symbol":["CD3EAP"]},"alphafold":{"accession":"O15446","domains":[{"cath_id":"-","chopping":"33-52_60-120","consensus_level":"high","plddt":90.4568,"start":33,"end":120}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15446","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15446-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15446-F1-predicted_aligned_error_v6.png","plddt_mean":55.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=POLR1G","jax_strain_url":"https://www.jax.org/strain/search?query=POLR1G"},"sequence":{"accession":"O15446","fasta_url":"https://rest.uniprot.org/uniprotkb/O15446.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15446/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15446"}},"corpus_meta":[{"pmid":"10675905","id":"PMC_10675905","title":"Integrin signalling: a new Cas(t) of characters enters the stage.","date":"2000","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10675905","citation_count":258,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8973158","id":"PMC_8973158","title":"Directing alternative splicing: cast and scenarios.","date":"1996","source":"Trends in genetics : TIG","url":"https://pubmed.ncbi.nlm.nih.gov/8973158","citation_count":185,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19189073","id":"PMC_19189073","title":"Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response.","date":"2009","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/19189073","citation_count":180,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33626327","id":"PMC_33626327","title":"Quantitative evaluation of chromosomal rearrangements in gene-edited human stem cells by CAST-Seq.","date":"2021","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/33626327","citation_count":166,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1737851","id":"PMC_1737851","title":"Pathobiology of cast nephropathy from human Bence Jones proteins.","date":"1992","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/1737851","citation_count":159,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14734538","id":"PMC_14734538","title":"Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release.","date":"2004","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14734538","citation_count":158,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11420714","id":"PMC_11420714","title":"Chromatin remodeling and transcriptional activation: the cast (in order of appearance).","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11420714","citation_count":157,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17222907","id":"PMC_17222907","title":"Fish cast NETs: neutrophil extracellular traps are released from fish neutrophils.","date":"2006","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17222907","citation_count":136,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10556421","id":"PMC_10556421","title":"Quantitative trait loci for bone density in C57BL/6J and CAST/EiJ inbred mice.","date":"1999","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/10556421","citation_count":135,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16751537","id":"PMC_16751537","title":"Use of copper cast alloys to control Escherichia coli O157 cross-contamination during food processing.","date":"2006","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16751537","citation_count":109,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35484322","id":"PMC_35484322","title":"Disentangling the relative importance of T cell responses in COVID-19: leading actors or supporting cast?","date":"2022","source":"Nature reviews. 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\"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (co-IP, in vitro transcription, antibody inhibition, excess protein competition) in a single study with rigorous controls\",\n      \"pmids\": [\"16809778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"POLR1G (CAST/hPAF49) undergoes growth-regulated tyrosine phosphorylation specifically in initiation-competent Pol Iβ complexes in HeLa cells, at a conserved residue also important for T-cell signaling.\",\n      \"method\": \"Phosphorylation analysis in HeLa cell Pol I complexes; biochemical fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single study, biochemical fractionation with phosphorylation analysis\",\n      \"pmids\": [\"16809778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse PAF49 (ortholog of human POLR1G) co-purifies with a subpopulation of RNA Pol I, physically associates with Pol I by co-immunoprecipitation, interacts with PAF53 through its N-terminal segment, and interacts with TAF(I)48 (the 48-kDa subunit of SL1); anti-PAF49 antibody severely impairs specific in vitro transcription from the mouse rRNA promoter, which is rescued by recombinant PAF49.\",\n      \"method\": \"Co-purification, co-immunoprecipitation, in vitro transcription with antibody inhibition and rescue, overexpression of deletion mutants in vivo, immunolocalization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro transcription reconstitution with antibody inhibition and recombinant rescue, plus co-IP and in vivo overexpression\",\n      \"pmids\": [\"15226435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse PAF49 (POLR1G ortholog) localizes to the nucleolus in actively growing cells but disperses to the nucleoplasm in growth-arrested cells, linking its nucleolar localization to active rRNA transcription.\",\n      \"method\": \"Immunolocalization in growing vs. growth-arrested cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment tied to functional (growth) state\",\n      \"pmids\": [\"15226435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Yeast A34.5 (ortholog of POLR1G) is a phosphoprotein that co-purifies with RNA Pol I; its deletion causes structural modification of purified Pol I (also losing subunit A49), and triple mutants lacking A34.5, A49, and A12.2 are viable but inactivating any of these together with A14 is lethal, rescued by Pol II-driven pre-rRNA expression; A34.5 becomes quasi-essential when DNA topoisomerase I is absent, suggesting a specific role in overcoming topological constraints during rDNA transcription.\",\n      \"method\": \"Genetic deletion analysis, in vivo growth assays, synthetic lethality epistasis, Pol II promoter rescue, in vitro purification of mutant Pol I\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis with Pol II rescue experiment, multiple mutant combinations, and in vitro enzyme characterization; independently foundational yeast study\",\n      \"pmids\": [\"9121426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mammalian PAF49 and PAF53 form a heterodimer; the heterodimerization domain of PAF49 maps to amino acids 41-86, consistent with structural homology to yeast A34.5-A49; substitution of yeast A34.5 residues 52-98 with PAF49 residues 41-86 allows heterodimerization with mouse PAF53, confirming structural conservation.\",\n      \"method\": \"Deletion mutagenesis, substitution mutagenesis, co-immunoprecipitation, in silico structural prediction\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — deletion and substitution mutagenesis with co-IP validation in single study\",\n      \"pmids\": [\"22849406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The PAF49/PAF53 heterodimer (containing POLR1G/PAF49) is acetylated on multiple sites of PAF49; hypoacetylated heterodimer binds Pol I with greater affinity than acetylated heterodimer; the heterodimer interacts with Rrn3, suggesting it facilitates Rrn3 recruitment to Pol I, which is essential for transcription initiation.\",\n      \"method\": \"Co-immunoprecipitation, acetylation analysis, affinity binding assays, nucleolar localization studies\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP and biochemical binding assays in single study; multiple orthogonal approaches but not reconstituted in vitro\",\n      \"pmids\": [\"25225125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structures of yeast Pol I elongation complexes (containing the A34.5/POLR1G ortholog as part of the A49-A34.5 heterodimer) reveal that most nucleotide-bound elongation complexes lack the A49-A34.5 heterodimer and adopt a Pol II-like conformation with A12.2 C-terminal domain in a previously unobserved position; this suggests reversible binding of the A49-A34.5 heterodimer contributes to regulation of Pol I transcription initiation and elongation.\",\n      \"method\": \"Cryo-electron microscopy at 3.2-3.4 Å resolution with biochemical validation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure with functional interpretation and biochemical data\",\n      \"pmids\": [\"30913026\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POLR1G (PAF49/hPAF49) is a Pol I-specific subunit that forms a heterodimer with PAF53 (homologous to the yeast A34.5-A49 TFIIF-like subcomplex), associates with initiation-competent Pol I complexes, undergoes growth-regulated tyrosine phosphorylation and acetylation that modulate its binding affinity to Pol I and Rrn3, interacts with the transcription activator UBF to stimulate rDNA transcription beyond basal levels, and dissociates reversibly from the elongation complex—consistent with a regulatory role in both transcription initiation and elongation by RNA polymerase I.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification of key papers:**\n\n- Papers [1]-[13] in main corpus (CAST as integrin/synaptic/nephropathy/etc.): EXCLUDE — alias collision (different \"CAST\" proteins)\n- Paper [26] main corpus: KEEP — A34.5, yeast RNA Pol I subunit, ortholog of POLR1G/PAF49\n- Paper [44] main corpus: KEEP — CAST/hPAF49, human RNA Pol I-specific subunit\n- Paper [45] main corpus: KEEP — PAF49, mouse RNA Pol I-associated factor\n- Paper [51] main corpus: KEEP — cryo-EM of yeast Pol I with A49-A34.5 heterodimer\n- Paper [60] main corpus: KEEP — SAD1/RPA34.5 rice ortholog of A34.5 (POLR1G ortholog)\n- Paper [91] additional curated: KEEP — PAF49/PAF53 interactions, mammalian Pol I\n- Paper [92] additional curated: KEEP — PAF49/PAF53 heterodimer regulation, Pol I\n- Papers [1],[2],[3],[4],[5],[6],[7],[8],[9],[10] additional curated: partial KEEP for interactome data touching POLR1G\n- Paper [21] additional curated: KEEP — basic mechanisms in Pol I transcription (reviews POLR1G context)\n- Paper [27] additional curated: KEEP — FACT and Pol I transcription\n- Paper [61] main corpus: KEEP — RPA34 (Xenopus ortholog), replication/Pol I context — actually RPA34 here refers to Replication Protein A subunit, NOT RNA Pol I subunit. EXCLUDE.\n- Paper [86] main corpus: KEEP (mentions POLR1G SNP interactions in lung cancer — but this is expression/association only, no mechanism). EXCLUDE from discoveries.\n\nAll other main corpus papers are alias collisions (synaptic CAST, calpastatin CAST, casting materials, etc.) — EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The yeast RNA Pol I-specific subunit A34.5 (ortholog of human POLR1G/PAF49) is a phosphoprotein that copurifies with RNA Pol I and is required for stable association of subunit A49 with the enzyme; cells lacking A34.5 produce a structurally altered, catalytically active Pol I that lacks A49 upon in vitro purification. Genetic epistasis showed that A34.5 becomes quasi-essential in strains lacking DNA topoisomerase I, suggesting a specific role in helping Pol I overcome topological constraints during rDNA transcription. Synthetic lethality with A14 deletion (rescued by Pol II-driven pre-rRNA) demonstrated that A34.5 is collectively essential for rRNA synthesis.\",\n      \"method\": \"Genetic deletion analysis, in vitro purification/reconstitution of RNA Pol I, complementation by Pol II-driven pre-rRNA, double and triple mutant epistasis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal genetic and biochemical methods in a single rigorous study; reconstitution of mutant enzyme in vitro with clear phenotypic readouts\",\n      \"pmids\": [\"9121426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse PAF49 (ortholog of human POLR1G) copurifies and coimmunoprecipitates with a transcriptionally active subpopulation of RNA Pol I. PAF49 physically interacts with PAF53 through its N-terminal segment, and this same region interacts with TAF(I)48 (a subunit of SL1/selectivity factor), pulling down the entire SL1 complex. Anti-PAF49 antibody severely impairs specific rDNA transcription in vitro, an effect rescued by recombinant PAF49. Overexpression of a PAF49 deletion mutant reduces pre-rRNA synthesis in vivo. PAF49 localizes to the nucleolus in growing cells but disperses to the nucleoplasm in growth-arrested cells.\",\n      \"method\": \"Coimmunoprecipitation, in vitro transcription assay with antibody inhibition and recombinant protein rescue, immunolocalization, overexpression of dominant-negative deletion mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, in vitro transcription inhibition/rescue, dominant-negative OE, localization) in a single study with clear functional readouts\",\n      \"pmids\": [\"15226435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human CAST/hPAF49 (POLR1G) is a bona fide RNA Pol I-specific subunit present in initiation-competent Pol Iβ complexes in HeLa cells. It undergoes growth-regulated tyrosine phosphorylation at a conserved residue. CAST/hPAF49 interacts with the activator UBF and weakly with SL1 at the rDNA promoter. CAST/hPAF49-specific antibodies and excess CAST/hPAF49 protein inhibit UBF-activated (but not basal) Pol I transcription after SL1-Pol I-rDNA complex assembly, and disrupt the UBF–CAST/hPAF49 interaction, indicating that the interaction of this Pol I-specific subunit with UBF is required for transcriptional activation.\",\n      \"method\": \"Biochemical purification of Pol I complexes, coimmunoprecipitation, in vitro transcription inhibition assays with antibodies and recombinant protein, phosphorylation analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, in vitro transcription with antibody and excess protein inhibition, phosphorylation mapping) establishing mechanism; strong within single study\",\n      \"pmids\": [\"16809778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mammalian PAF49 (POLR1G) and PAF53 form a heterodimer, and deletion mutagenesis identified that amino acids 41–86 of PAF49 are sufficient for heterodimerization with PAF53. This region is structurally analogous to yeast A34.5 residues 52–98, and substituting the yeast A34.5 sequence with mammalian PAF49 residues 41–86 enabled interspecific heterodimerization with mouse PAF53, confirming conserved structural organization. The mammalian PAF49/PAF53 heterodimer is the functional equivalent of the yeast A34.5/A49 TFIIF-like subcomplex.\",\n      \"method\": \"Deletion and substitution mutagenesis of PAF49 and PAF53, coimmunoprecipitation of heterodimers, in silico structural prediction\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal deletion mutagenesis with Co-IP, single lab, supported by structural analogy to yeast system\",\n      \"pmids\": [\"22849406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The association of the PAF49/PAF53 (POLR1G-containing) heterodimer with RNA Pol I is regulated: PAF49 is acetylated on multiple sites, and hypoacetylated PAF49/PAF53 heterodimer binds Pol I with greater affinity than acetylated heterodimer. The heterodimer also physically interacts with Rrn3, and this interaction is proposed to facilitate recruitment of Rrn3 to Pol I, linking the heterodimer to transcription initiation. Nucleolar levels of PAF49/PAF53 are regulated independently of total protein levels.\",\n      \"method\": \"Coimmunoprecipitation, acetylation analysis, subcellular fractionation/nucleolar localization, protein interaction assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and acetylation mapping in single lab, moderate mechanistic follow-up\",\n      \"pmids\": [\"25225125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structures of yeast RNA Pol I elongation complexes at 3.2–3.4 Å resolution reveal that the A49–A34.5 (POLR1G ortholog) heterodimer is dissociated from most nucleotide-bound elongation complexes, which instead adopt a Pol II-like conformation. In the absence of the heterodimer, the A12.2 C-terminal domain occupies a previously unobserved position at the A135 surface. This structural and biochemical data supports a model in which reversible binding of the A49–A34.5 heterodimer regulates the transition between transcription initiation and elongation states of Pol I.\",\n      \"method\": \"Cryo-electron microscopy at 3.2–3.4 Å resolution, biochemical reconstitution of elongation complexes with nucleotide analog GMPCPP\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic resolution cryo-EM structure with biochemical validation, revealing specific functional conformational states\",\n      \"pmids\": [\"30913026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The histone chaperone FACT (SSRP1 and Spt16 subunits) co-purifies and co-immunoprecipitates with mammalian RNA Pol I complexes (which contain PAF49/POLR1G). siRNA-mediated depletion of FACT subunits significantly reduces 47S pre-rRNA levels without affecting synthesis of the first 40 nt of rRNA, indicating FACT is required for Pol I transcription elongation through chromatin. This places POLR1G-containing Pol I complexes in a pathway requiring FACT for chromatin template transcription.\",\n      \"method\": \"Coimmunoprecipitation of FACT with Pol I, siRNA knockdown of FACT subunits with pre-rRNA level measurement, ChIP at rDNA loci\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional siRNA knockdown with defined phenotype, single lab\",\n      \"pmids\": [\"19214185\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POLR1G (human PAF49/CAST/hPAF49; yeast ortholog A34.5) is a Pol I-specific subunit that forms a TFIIF-like heterodimer with PAF53 (A49), associates with transcription-initiation-competent Pol I complexes in the nucleolus, undergoes growth-regulated tyrosine phosphorylation, interacts with the transcriptional activator UBF to stimulate rDNA transcription beyond basal levels, and whose reversible dissociation from the elongation complex (as shown by cryo-EM) is proposed to regulate the switch between Pol I initiation and elongation; acetylation of PAF49 modulates its affinity for Pol I and facilitates Rrn3 recruitment, while the A34.5 yeast ortholog helps Pol I overcome topological constraints during rDNA transcription.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"POLR1G (also known as PAF49/CAST) is a Pol I-specific subunit that heterodimerizes with PAF53 through a conserved N-terminal domain (residues 41–86) to form the mammalian counterpart of the yeast A34.5–A49 TFIIF-like subcomplex, which reversibly associates with RNA polymerase I to regulate rDNA transcription initiation and elongation [PMID:22849406, PMID:30913026]. POLR1G interacts with the transcription activator UBF and with SL1/TAF(I)48 at the rDNA promoter, and this interaction is specifically required for UBF-activated—but not basal—Pol I transcription [PMID:16809778, PMID:15226435]. Post-translational modifications regulate its function: growth-dependent tyrosine phosphorylation marks the initiation-competent Pol Iβ complex, while acetylation of the PAF49–PAF53 heterodimer modulates its binding affinity to Pol I and to the initiation factor Rrn3 [PMID:16809778, PMID:25225125]. In yeast, loss of the A34.5 ortholog is tolerated but becomes quasi-essential in the absence of DNA topoisomerase I, indicating a role in resolving topological constraints during rDNA transcription [PMID:9121426].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that the A34.5 subunit (yeast POLR1G ortholog) is a dispensable but conditionally essential Pol I component resolved whether it was required for core transcription or played a regulatory role—its synthetic lethality with topoisomerase I loss pointed to a function in managing topological stress during rDNA transcription.\",\n      \"evidence\": \"Genetic deletion, synthetic lethality epistasis, and Pol II promoter rescue in S. cerevisiae\",\n      \"pmids\": [\"9121426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct biochemical activity assigned to A34.5 itself\",\n        \"Mechanism by which A34.5 aids topological resolution unknown\",\n        \"Mammalian relevance not yet tested\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that mouse PAF49 physically associates with a Pol I subpopulation, heterodimerizes with PAF53, interacts with SL1/TAF(I)48, and is required for rDNA promoter-specific transcription established POLR1G as a bona fide Pol I subunit with a role in promoter-directed initiation.\",\n      \"evidence\": \"Co-purification, co-IP, in vitro transcription with antibody inhibition and recombinant rescue, immunolocalization in mouse cells\",\n      \"pmids\": [\"15226435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which step of initiation PAF49 promotes was not resolved\",\n        \"Relationship to UBF-dependent activation unknown\",\n        \"Whether PAF49 participates in elongation was untested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying POLR1G's direct interaction with UBF and showing that antibody or excess POLR1G selectively blocks UBF-activated (but not basal) transcription revealed that POLR1G transduces the activating signal from UBF to the Pol I machinery.\",\n      \"evidence\": \"Co-IP, in vitro transcription with antibody inhibition and recombinant competition in HeLa cells\",\n      \"pmids\": [\"16809778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the kinase mediating growth-regulated tyrosine phosphorylation unknown\",\n        \"Structural basis of POLR1G–UBF interaction unresolved\",\n        \"In vivo loss-of-function in mammalian cells not performed\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping the PAF49–PAF53 heterodimerization interface to PAF49 residues 41–86 and showing functional interchangeability with yeast A34.5 confirmed that the TFIIF-like heterodimer architecture is structurally conserved from yeast to mammals.\",\n      \"evidence\": \"Deletion and substitution mutagenesis with co-IP validation\",\n      \"pmids\": [\"22849406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of the mammalian heterodimer\",\n        \"Functional consequences of disrupting the dimerization interface in vivo not tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that acetylation of the PAF49–PAF53 heterodimer reduces its affinity for Pol I and that the heterodimer contacts Rrn3 introduced a post-translational regulatory mechanism linking POLR1G modification state to Pol I initiation competence.\",\n      \"evidence\": \"Co-IP, acetylation analysis, and affinity binding assays in mammalian cells\",\n      \"pmids\": [\"25225125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Acetyltransferase and deacetylase acting on PAF49 not identified\",\n        \"In vivo functional impact of acetylation-site mutations not tested\",\n        \"Relationship between phosphorylation and acetylation marks unclear\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"High-resolution cryo-EM structures of yeast Pol I elongation complexes revealed that the A49–A34.5 heterodimer dissociates from most nucleotide-bound complexes, establishing that reversible binding of the POLR1G-containing subcomplex is a structural switch between initiation-competent and elongation conformations.\",\n      \"evidence\": \"Cryo-EM at 3.2–3.4 Å resolution with biochemical validation in S. cerevisiae\",\n      \"pmids\": [\"30913026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether dissociation is actively regulated or stochastic is unresolved\",\n        \"No mammalian elongation complex structure available\",\n        \"Functional consequence of preventing heterodimer dissociation untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of kinases and acetyltransferases that modify POLR1G, the structural basis of its interaction with UBF, and its in vivo requirement in mammalian rDNA transcription remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No mammalian genetic loss-of-function or disease association established\",\n        \"Full structural model of the mammalian POLR1G–PAF53–Pol I assembly unavailable\",\n        \"Mechanism coupling POLR1G modification to growth-signal integration unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 4, 7]}\n    ],\n    \"complexes\": [\n      \"RNA polymerase I\",\n      \"PAF49-PAF53 heterodimer (TFIIF-like subcomplex)\"\n    ],\n    \"partners\": [\n      \"POLR1F\",\n      \"UBF\",\n      \"RRDN3\",\n      \"TAF1A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"POLR1G (PAF49/CAST/A34.5) is an RNA polymerase I-specific subunit that forms a TFIIF-like heterodimer with PAF53 (A49) and is required for stable incorporation of PAF53 into the Pol I enzyme and for activated rDNA transcription [PMID:9121426, PMID:22849406]. Within initiation-competent Pol Iβ complexes in the nucleolus, POLR1G undergoes growth-regulated tyrosine phosphorylation and interacts with the transcriptional activator UBF to enable UBF-dependent (but not basal) transcription, while acetylation of POLR1G modulates its affinity for Pol I and facilitates Rrn3 recruitment [PMID:16809778, PMID:25225125]. Cryo-EM structures of yeast Pol I elongation complexes show that the A49–A34.5 heterodimer reversibly dissociates during elongation, adopting a Pol II-like conformation, supporting a model in which POLR1G regulates the switch between transcription initiation and elongation [PMID:30913026]. In yeast, the A34.5 ortholog becomes quasi-essential in strains lacking DNA topoisomerase I, indicating a role in overcoming topological constraints during rDNA transcription [PMID:9121426].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that A34.5 (POLR1G ortholog) is a Pol I-specific subunit required for stable A49 association and collectively essential for rRNA synthesis answered the foundational question of whether this subunit has a dedicated role in Pol I rather than being a loosely associated factor.\",\n      \"evidence\": \"Genetic deletion, in vitro Pol I purification/reconstitution, and synthetic lethality analysis in yeast\",\n      \"pmids\": [\"9121426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which A34.5 helps Pol I overcome topological constraints not determined at molecular level\",\n        \"Whether loss of A34.5 affects transcription initiation, elongation, or both was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that mammalian PAF49 copurifies with transcriptionally active Pol I, interacts with PAF53 and SL1, and is required for rDNA transcription established its conserved role as a functional Pol I subunit bridging the enzyme to the initiation machinery.\",\n      \"evidence\": \"Co-IP, antibody-mediated in vitro transcription inhibition with recombinant protein rescue, dominant-negative overexpression, and nucleolar immunolocalization in mouse cells\",\n      \"pmids\": [\"15226435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the PAF49–SL1 interaction is direct or mediated through TAF(I)48 exclusively was not resolved\",\n        \"Growth-regulated mechanism controlling PAF49 nucleolar versus nucleoplasmic redistribution unknown\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying that POLR1G undergoes growth-regulated tyrosine phosphorylation and that its interaction with UBF is specifically required for activated (not basal) Pol I transcription resolved how Pol I-specific subunits transduce activator signals during rDNA transcription.\",\n      \"evidence\": \"Biochemical purification, Co-IP, in vitro transcription assays with antibody and excess protein inhibition in HeLa cells\",\n      \"pmids\": [\"16809778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the kinase responsible for growth-regulated tyrosine phosphorylation not determined\",\n        \"Functional consequence of tyrosine phosphorylation on UBF interaction or transcription not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The finding that the histone chaperone FACT co-purifies with POLR1G-containing Pol I and is required for Pol I elongation through chromatin placed POLR1G in a chromatin-dependent elongation pathway.\",\n      \"evidence\": \"Co-IP of FACT with Pol I and siRNA knockdown with pre-rRNA measurement in mammalian cells\",\n      \"pmids\": [\"19214185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether POLR1G/PAF49 directly contacts FACT or is merely a co-resident in the same Pol I complex is unresolved\",\n        \"Effect of PAF49 depletion on FACT recruitment not tested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping the minimal PAF49 heterodimerization domain (aa 41–86) and demonstrating interspecific heterodimerization with yeast A34.5 sequences confirmed structural conservation of the TFIIF-like architecture across eukaryotes.\",\n      \"evidence\": \"Deletion and substitution mutagenesis with Co-IP of heterodimers\",\n      \"pmids\": [\"22849406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of the mammalian PAF49–PAF53 heterodimer\",\n        \"Functional consequence of disrupting specific residues within the dimerization domain not tested in transcription assays\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealing that acetylation of PAF49 reduces its affinity for Pol I and that the PAF49/PAF53 heterodimer interacts with Rrn3 linked post-translational modification of POLR1G to regulation of Pol I initiation factor recruitment.\",\n      \"evidence\": \"Co-IP, acetylation mapping, and nucleolar fractionation in mammalian cells\",\n      \"pmids\": [\"25225125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Acetyltransferase and deacetylase acting on PAF49 not identified\",\n        \"Whether acetylation directly regulates Rrn3 recruitment in vivo not demonstrated\",\n        \"Functional impact of individual acetylation sites not resolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Near-atomic cryo-EM structures showing that the A49–A34.5 heterodimer dissociates from Pol I during elongation, with the enzyme adopting a Pol II-like conformation, provided the structural basis for the model that POLR1G reversibly regulates the initiation-to-elongation transition.\",\n      \"evidence\": \"Cryo-EM at 3.2–3.4 Å of yeast Pol I elongation complexes with biochemical reconstitution\",\n      \"pmids\": [\"30913026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Dynamics of heterodimer dissociation and re-association in living cells not measured\",\n        \"Whether mammalian PAF49–PAF53 undergoes the same dissociation during elongation not confirmed\",\n        \"Signals or factors triggering heterodimer release remain unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The kinase(s) responsible for growth-regulated tyrosine phosphorylation of POLR1G, the acetyltransferase/deacetylase pair controlling its acetylation state, and whether heterodimer dissociation during elongation occurs in mammalian Pol I remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of the mammalian PAF49–PAF53 heterodimer exists\",\n        \"In vivo dynamics of heterodimer association with Pol I during the transcription cycle are uncharacterized\",\n        \"How tyrosine phosphorylation and acetylation are coordinated to regulate POLR1G function is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 5]}\n    ],\n    \"complexes\": [\n      \"RNA polymerase I\",\n      \"PAF49-PAF53 (A34.5-A49) TFIIF-like heterodimer\"\n    ],\n    \"partners\": [\n      \"POLR1E\",\n      \"UBF\",\n      \"RRN3\",\n      \"TAF1A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}