Affinage

POLR1F

DNA-directed RNA polymerase I subunit RPA43 · UniProt Q3B726

Length
338 aa
Mass
37.4 kDa
Annotated
2026-06-10
10 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/4 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POLR1F (A43/RPA43) is an essential subunit of RNA Polymerase I required for synthesis of 35S rRNA, its inactivation being lethal and specifically abolishing rRNA production without affecting Pol II or Pol III transcription (PMID:7592632). Within Pol I it forms a tight heterodimer with the A14 subunit—the structural and functional counterpart of the Pol II Rpb4/Rpb7 stalk—and is required to stabilize both A14 and the common subunit ABC23 in the assembled enzyme (PMID:12407181); the recombinant A14/A43 heterodimer binds single-stranded RNA, paralleling the archaeal E/F complex (PMID:12888498). A43 couples Pol I to promoter recruitment by directly binding the transcription factor Rrn3 to form the transcriptionally competent Pol I–Rrn3 complex needed for rDNA promoter engagement (PMID:11032814), and genetically interacts with the elongation factor Spt5 and the non-essential elongation subunits Rpa12, Rpa34, and Rpa49 (PMID:21983101). In human cells RPA43 promotes recruitment of Pol I machinery to the rDNA promoter, drives rRNA accumulation and proliferation, and restrains migration by dampening c-JUN and Integrin expression (PMID:37343605); it additionally enhances H3K4 trimethylation at the F2R promoter by limiting KDM5C binding, thereby activating F2R transcription and downstream p38 MAPK signaling to support tumor cell proliferation and stemness (PMID:40250711).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1995 High

    Established that A43/RPA43 is an essential, dedicated component of the rRNA transcription apparatus rather than a shared polymerase factor, defining its core biological purpose.

    Evidence Gene inactivation with GAL7-35SrDNA rescue and [3H]uridine pulse labeling of RNA products in yeast

    PMID:7592632

    Open questions at the time
    • Did not resolve which Pol I subassembly A43 belongs to
    • Function of the acidic C-terminal domain and its phosphorylation not defined
    • No mechanism for how loss abolishes 35S rRNA synthesis
  2. 2000 High

    Answered how Pol I is recruited to rDNA promoters by showing A43 directly bridges the polymerase to the initiation factor Rrn3.

    Evidence Genetic epistasis, E. coli co-expression, two-hybrid, affinity chromatography, and immunoEM in yeast

    PMID:11032814

    Open questions at the time
    • Structural basis of the A43–Rrn3 interface not resolved
    • How the Pol I–Rrn3 complex is regulated/disassembled not addressed
  3. 2002 High

    Placed A43 architecturally within Pol I as a stalk subunit, defining the A43–A14 heterodimer as the Pol I equivalent of the Pol II Rpb4–Rpb7 pair and showing A43 stabilizes A14 and ABC23.

    Evidence Biochemical co-purification, genetic analysis, and immunoEM in yeast

    PMID:12407181

    Open questions at the time
    • Atomic-resolution position within the holoenzyme not determined here
    • Functional consequence of stalk RNA contact not tested
  4. 2003 Medium

    Demonstrated a biochemical activity for the stalk by showing the reconstituted A14/A43 heterodimer binds single-stranded RNA, analogous to the archaeal E/F complex.

    Evidence Recombinant co-expression/co-purification, EMSA, and sequence/structural analysis

    PMID:12888498

    Open questions at the time
    • Physiological RNA substrate and in vivo relevance of RNA binding not established
    • HRDC domain assignment for A14 is computational inference
  5. 2008 Medium

    Provided a structural foothold by crystallizing the A14/A43 heterodimer subcomplex after trimming flexible regions.

    Evidence X-ray crystallography (crystallization reported) of the isolated subcomplex

    PMID:18453714

    Open questions at the time
    • Full functional validation not described
    • Heterodimer crystallized in isolation, not within the holoenzyme
  6. 2011 Medium

    Linked A43 to transcription elongation by mapping dispensable hydrophilic domains that genetically interact with elongation subunits and showing direct binding to Spt5.

    Evidence Deletion mapping, domain swapping, genetic interaction, and two-hybrid in yeast/S. pombe

    PMID:21983101

    Open questions at the time
    • Spt6 interaction only suggested, not confirmed
    • Mechanism by which A43 modulates elongation not defined
    • Two-hybrid Spt5 interaction lacks reciprocal in vitro validation
  7. 2023 Medium

    Extended A43 function to human cells, showing RPA43 promotes Pol I machinery recruitment and proliferation while restraining migration via c-JUN and Integrin.

    Evidence RPA43 knockdown in HeLa cells with rDNA promoter ChIP, proliferation and migration assays

    PMID:37343605

    Open questions at the time
    • Direct link between Pol I recruitment and the migration phenotype not mechanistically separated
    • Single cell line; no in vivo confirmation in this study
  8. 2025 Medium

    Identified a non-canonical chromatin role: POLR1F enhances H3K4me3 at the F2R promoter by excluding KDM5C, activating F2R and p38 MAPK signaling to drive tumor growth.

    Evidence siRNA knockdown, RNA-seq, ChIP for H3K4me3/KDM5C, and zebrafish/mouse xenografts

    PMID:40250711

    Open questions at the time
    • How a Pol I stalk subunit influences H3K4me3/KDM5C occupancy mechanistically is unresolved
    • Whether this is independent of its Pol I function is unclear
    • Direct binding of POLR1F to the F2R locus or KDM5C not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How POLR1F's canonical Pol I stalk role mechanistically connects to its human chromatin/signaling functions (F2R/H3K4me3, c-JUN/Integrin, p38 MAPK) remains unresolved.
  • No structural model of human POLR1F within Pol I
  • Mechanism coupling Pol I transcription to F2R regulation and migration not defined
  • Whether non-canonical roles are direct or secondary to altered rRNA output untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0005198 structural molecule activity 2 GO:0003723 RNA binding 1
Localization
GO:0005730 nucleolus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 3
Partners
A14ABC23KDM5CRRN3SPT5
Complex memberships
A14/A43 stalk heterodimerPol I-Rrn3 complexRNA Polymerase I

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Yeast A43 (POLR1F ortholog) directly interacts with transcription factor Rrn3 to form the transcriptionally competent Pol I–Rrn3 complex required for rDNA promoter recruitment; conditional mutations in A43 disrupt this complex, the two proteins form a stable complex when co-expressed in E. coli, Rrn3 overexpression suppresses A43 mutant phenotype, and A43/Rrn3 double mutants show synthetic lethality. Genetic epistasis (conditional mutations, suppressor overexpression, synthetic lethality), co-expression in E. coli, immunoelectron microscopy co-localization, two-hybrid screen, affinity chromatography The EMBO journal High 11032814
2002 Yeast A43 forms a stable heterodimer with Pol I subunit A14 and interacts with the common subunit ABC23; A43 is required for stabilization of both A14 and ABC23 within Pol I; immunoelectron microscopy places A43, A14, and ABC23 together in the Pol I three-dimensional structure; the A43–A14 pair is the Pol I counterpart of the Rpb7–Rpb4 heterodimer of Pol II. Biochemical co-purification, genetic analysis, immunoelectron microscopy Proceedings of the National Academy of Sciences of the United States of America High 12407181
1995 RPA43/A43 is an essential subunit of yeast RNA polymerase I; gene inactivation is lethal and abolishes 35S rRNA synthesis without affecting Pol II or Pol III products; A43 is a phosphoprotein with a strongly acidic C-terminal domain. Gene inactivation (lethal phenotype rescued by GAL7-35SrDNA), [3H]uridine pulse labeling of RNA products, nonsense allele analysis The Journal of biological chemistry High 7592632
2003 Recombinant A14/A43 heterodimer can be co-expressed and co-purified, confirming a tight specific interaction; the heterodimer binds single-stranded RNA as shown by gel mobility shift assays, analogous to the archaeal E/F complex; A14 contains a predicted HRDC domain structurally linking it to the RPB4/C17/subunit F family. Recombinant co-expression and co-purification, gel mobility shift assay (EMSA), sequence/structural analysis Nucleic acids research Medium 12888498
2008 The A14/A43 heterodimer subcomplex of RNA polymerase I was crystallized after iterative removal of flexible regions, enabling structural analysis of this subunit pair. X-ray crystallography (crystallization reported; structure solution implied for hybrid approaches) Acta crystallographica. Section F, Structural biology and crystallization communications Medium 18453714
2011 Deletion mapping and domain swapping with S. pombe show that the hydrophilic domains of Rpa43 unique to fungi/vertebrates are dispensable for growth but genetically interact with rpa12Δ, rpa34Δ, and rpa49Δ (non-essential subunits for elongation); two-hybrid and genetic data indicate Rpa43 directly binds elongation factor Spt5 and may interact with nucleosomal chaperone Spt6. Deletion mapping, domain swapping, genetic interaction analysis, yeast two-hybrid FEBS letters Medium 21983101
2023 Human RPA43 (POLR1F) positively modulates recruitment of Pol I transcription machinery factors to the rDNA promoter, activates rRNA accumulation and cell proliferation, and inhibits cell migration by dampening expression of c-JUN and Integrin; RPA43 depletion promotes HeLa cell migration. RPA43 knockdown in HeLa cells, rDNA promoter ChIP (recruitment assay), cell proliferation and migration assays Biochimica et biophysica acta. General subjects Medium 37343605
2025 POLR1F (human) promotes H3K4 methylation at the F2R promoter by reducing binding of demethylase KDM5C to H3K4me3, thereby enhancing F2R transcription and activating downstream p38 MAPK signaling to support ATC cell proliferation and stemness; POLR1F knockdown reduces tumor growth in zebrafish and mouse xenograft models. POLR1F siRNA knockdown, RNA sequencing, ChIP for H3K4me3 and KDM5C at F2R promoter, in vivo xenograft (zebrafish and nude mouse) Biochimica et biophysica acta. Molecular cell research Medium 40250711

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The recruitment of RNA polymerase I on rDNA is mediated by the interaction of the A43 subunit with Rrn3. The EMBO journal 147 11032814
2002 The A14-A43 heterodimer subunit in yeast RNA pol I and their relationship to Rpb4-Rpb7 pol II subunits. Proceedings of the National Academy of Sciences of the United States of America 43 12407181
1995 Gene RPA43 in Saccharomyces cerevisiae encodes an essential subunit of RNA polymerase I. The Journal of biological chemistry 37 7592632
2003 Structural and functional homology between the RNAP(I) subunits A14/A43 and the archaeal RNAP subunits E/F. Nucleic acids research 24 12888498
2011 Rpa43 and its partners in the yeast RNA polymerase I transcription complex. FEBS letters 15 21983101
1999 [Characteristics of the cDNA of the Schizosaccharomyces pombe rpa43+ gene: structural similarity of the Rpa43 subunit of RNA-polymerase I with the Rpc25 subunit of RNA-polymerase III]. Bioorganicheskaia khimiia 11 10645483
2002 Identification and characterisation of the gene TWIST NEIGHBOR (TWISTNB) located in the microdeletion syndrome 7p21 region. Cytogenetic and genome research 10 12438708
2008 Crystallization of RNA polymerase I subcomplex A14/A43 by iterative prediction, probing and removal of flexible regions. Acta crystallographica. Section F, Structural biology and crystallization communications 6 18453714
2025 POLR1F promotes proliferation and stemness of anaplastic thyroid cancer by activating F2R/p38 MAPK signaling. Biochimica et biophysica acta. Molecular cell research 3 40250711
2023 RNA polymerase I subunit RPA43 activates rRNA expression and cell proliferation but inhibits cell migration. Biochimica et biophysica acta. General subjects 1 37343605

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