Affinage

RRN3

RNA polymerase I-specific transcription initiation factor RRN3 · UniProt Q9NYV6

Length
651 aa
Mass
74.1 kDa
Annotated
2026-04-28
39 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RRN3 (TIF-IA) is a conserved, growth-regulated RNA polymerase I transcription initiation factor that bridges Pol I to the rDNA promoter and couples nutrient/growth factor signaling to ribosome biogenesis. It adopts a HEAT repeat fold and directly engages the Pol I subunit RPA43 (via a phosphorylation-dependent interface) and the promoter selectivity factor SL1/TIF-IB (via a LARAK motif), converting inactive Pol I dimers into initiation-competent monomers; it also possesses intrinsic DNA-binding activity essential for transcription and functions stoichiometrically, becoming inactivated after each initiation round through CK2-mediated phosphorylation at Ser170/172, with FCP1 phosphatase recycling it for subsequent rounds (PMID:8413268, PMID:20, PMID:18559419, PMID:23393135). A multisite phosphorylation code integrates signals from ERK/RSK (Ser633/649), mTOR (Ser44/Ser199), JNK2 (Thr200), CK2, and Akt to control RRN3 activity, Pol I association, and nucleolar versus nucleoplasmic localization; genetic inactivation of RRN3 triggers nucleolar disruption, ribosomal protein L11-MDM2-dependent p53 stabilization, and apoptosis (PMID:12620228, PMID:15004009, PMID:15805466, PMID:15989966). Beyond canonical Pol I transcription, nutrient deprivation-induced Ser199 phosphorylation relocates RRN3 to the nucleoplasm where it regulates alternative polyadenylation of autophagy mRNAs, and during senescence ATM-dependent disruption of its interaction with SQSTM1/p62 drives nucleolar remodeling and SASP establishment (PMID:41271632, PMID:41466483).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1985 High

    Identification of TIF-IA as a growth-dependent factor required for Pol I transcription initiation established that rRNA synthesis is regulated at the level of a dissociable initiation factor whose activity is lost in quiescent cells.

    Evidence Biochemical fractionation and in vitro transcription reconstitution from mouse cell extracts

    PMID:4070001

    Open questions at the time
    • Molecular identity of TIF-IA unknown
    • No phosphorylation data
    • Mechanism of growth regulation unresolved
  2. 1993 High

    Demonstration that TIF-IA is a 75 kDa monomer that associates with Pol I, is required for the first phosphodiester bond but not preinitiation complex assembly, and is released after initiation revealed its stoichiometric, single-use nature in transcription.

    Evidence Purified reconstituted transcription system with template commitment assays

    PMID:2390974 PMID:8413268

    Open questions at the time
    • Gene identity not yet cloned
    • Mechanism of post-initiation release unknown
    • No structural information
  3. 1996 High

    Cloning of yeast RRN3 and demonstration that Rrn3p directly binds Pol I independently of DNA and stimulates promoter recruitment established RRN3 as the yeast counterpart of TIF-IA and a universal Pol I initiation factor.

    Evidence Immunoaffinity purification, in vitro transcription complementation, and Sarkosyl-resistant complex assays in yeast

    PMID:8670901

    Open questions at the time
    • Mammalian gene not yet cloned
    • Binding interface on Pol I unresolved
    • Phospho-regulatory mechanism unknown
  4. 2000 High

    Identification of the RPA43 subunit as the direct Rrn3 binding partner on Pol I, and Rrn6 (core factor) as the promoter-side contact, established the bridging model whereby Rrn3 physically connects Pol I to the promoter-bound core factor; concurrent cloning of mammalian TIF-IA as the RRN3 homolog confirmed functional conservation across eukaryotes.

    Evidence Genetic suppression, synthetic lethality, co-expression in E. coli, two-hybrid, yeast complementation with human RRN3

    PMID:10758157 PMID:11032814 PMID:11265758

    Open questions at the time
    • Detailed binding interface unresolved at atomic level
    • Phosphorylation sites not yet mapped in mammals
    • Mechanism of growth-dependent regulation still unclear
  5. 2002 High

    Mapping of TIF-IA interaction domains (aa 512–609 for Pol I, LARAK motif for SL1) and demonstration that phosphorylation state controls the Rrn3–Pol I interaction resolved how growth signals converge on TIF-IA at the molecular level.

    Evidence Deletion mutant mapping, co-immunoprecipitation, phosphatase treatment, comparison of phosphorylated vs. unphosphorylated recombinant Rrn3

    PMID:12015311 PMID:12393749

    Open questions at the time
    • Specific kinases not yet identified
    • Stoichiometric versus catalytic action still debated
    • Structural basis of phospho-regulation unknown
  6. 2003 High

    Identification of ERK/RSK phosphorylation at Ser633/649 as activating modifications directly linked MAPK growth factor signaling to Pol I transcription via TIF-IA, while demonstration that Rrn3 functions stoichiometrically (becoming inactivated after each round) explained why its continual reactivation is required.

    Evidence Phosphopeptide mapping, site-directed mutagenesis, kinase inhibitor treatment, in vivo rRNA synthesis assays, post-transcription reuse assays

    PMID:12620228 PMID:12646563

    Open questions at the time
    • Other regulatory kinases not yet identified
    • Mechanism of inactivation after initiation unclear
    • No structural data
  7. 2004 High

    Discovery that mTOR regulates TIF-IA via opposing phosphorylations at Ser44 (activating) and Ser199 (inactivating) established a second major signaling axis controlling Pol I transcription and showed that mTOR inhibition causes cytoplasmic translocation of TIF-IA.

    Evidence Rapamycin treatment, phosphomutant analysis, subcellular fractionation in mammalian cells

    PMID:15004009

    Open questions at the time
    • Direct mTOR kinase activity on TIF-IA not demonstrated
    • Relationship between mTOR and ERK/RSK inputs unclear
    • In vivo physiological relevance in whole organism not tested
  8. 2005 High

    Identification of JNK2-mediated Thr200 phosphorylation as a stress-responsive inactivating modification that disrupts both Pol I and SL1 interactions, and genetic demonstration that TIF-IA loss activates p53 via the RPL11-MDM2 pathway, placed TIF-IA at the nexus of nucleolar stress sensing.

    Evidence JNK2 kinase assays, site-directed mutagenesis, Jnk2-KO cells, TIF-IA conditional knockout in MEFs, co-IP of L11-MDM2

    PMID:15805466 PMID:15989966

    Open questions at the time
    • Whether JNK2 directly phosphorylates TIF-IA in vivo or acts through intermediary unclear
    • Full spectrum of stress signals converging on TIF-IA not mapped
    • Drosophila TOR-TIF-IA axis not yet confirmed
  9. 2007 High

    Conservation of TOR-dependent TIF-IA regulation in Drosophila and discovery that Pol I subunits Rpa34/Rpa49 regulate both Rrn3 recruitment and its post-initiation release broadened the mechanistic picture to include polymerase-intrinsic control of the Rrn3 cycle.

    Evidence Drosophila TIF-IA mutants with ChIP and TOR epistasis; yeast rpa49 mutant ChIP and polymerase occupancy assays

    PMID:18086878 PMID:18086911

    Open questions at the time
    • Structural basis of Rpa49-mediated Rrn3 release unknown
    • Whether mammalian PAF53/CAST ortholog has equivalent role not tested
  10. 2008 High

    Identification of CK2-mediated Ser170/172 phosphorylation as the trigger for TIF-IA release from RPA43 after initiation, and FCP1 phosphatase as the recycling enzyme, completed the phosphorylation cycle model explaining how TIF-IA is used stoichiometrically yet continuously recycled.

    Evidence In vitro kinase assay, site-directed mutagenesis, FRAP, ChIP, covalent tethering of TIF-IA to RPA43

    PMID:18559419

    Open questions at the time
    • Whether CK2 acts co-transcriptionally or post-initiation not resolved
    • Interplay between CK2 Ser170/172 and other phospho-sites unclear
    • Structural view of phospho-dependent release absent
  11. 2011 High

    The crystal structure of Rrn3 revealed a HEAT repeat fold with a surface serine patch whose phosphorylation blocks Pol I binding, providing the first atomic-level explanation for how phosphorylation acts as an on/off switch for Pol I initiation.

    Evidence X-ray crystallography, cross-linking mass spectrometry, phosphomimetic mutagenesis, ChIP, cell growth assays

    PMID:21940764

    Open questions at the time
    • No structure of the Pol I–Rrn3 complex at this point
    • How the serine patch integrates signals from multiple kinases structurally unresolved
  12. 2013 High

    Discovery that Rrn3 possesses intrinsic DNA-binding activity via an HSF2-like domain (aa 382–400) essential for transcription but dispensable for Pol I/SL1 binding revealed a previously unsuspected direct contact with the rDNA template.

    Evidence DNA-binding assays, domain mutagenesis, in vitro transcription, yeast complementation

    PMID:23393135

    Open questions at the time
    • Target DNA sequence specificity not defined
    • How DNA binding cooperates with Pol I/SL1 contacts structurally unknown
    • Whether DNA binding is regulated by phosphorylation untested
  13. 2016 High

    The cryo-EM structure of the Pol I–Rrn3 complex at 4.8 Å revealed that Rrn3 binding converts the inactive Pol I dimer into a monomeric initiation-competent form, providing the structural basis for the activation mechanism.

    Evidence Cryo-electron microscopy structural determination

    PMID:27418309

    Open questions at the time
    • Resolution insufficient for side-chain detail at interface
    • Ternary complex with promoter factors and DNA not captured
    • Mechanism of dimer disruption not fully resolved
  14. 2025 Medium

    Discovery that Ser199-phosphorylated RRN3 translocates to the nucleoplasm under nutrient deprivation and regulates alternative polyadenylation of autophagy mRNAs (e.g., OPTN) established a non-canonical, Pol I-independent function in mRNA metabolism and autophagy.

    Evidence Long-read RNA sequencing, PAR-CLIP, cellular fractionation, phosphomutant analysis, in vivo tumor xenograft

    PMID:41271632

    Open questions at the time
    • Mechanism of APA regulation (direct RNA binding vs. cofactor recruitment) not fully defined
    • Not independently replicated
    • Scope of target mRNAs beyond autophagy genes unclear
  15. 2026 Medium

    Identification of ATM-dependent disruption of the TIF-IA–SQSTM1/p62 interaction during senescence, leading to nuclear TIF-IA accumulation essential for SASP and nucleolar remodeling, extended TIF-IA function to senescence biology beyond its canonical Pol I role.

    Evidence Co-immunoprecipitation, ATM inhibition, oncogene- and therapy-induced senescence models, mouse models

    PMID:41466483

    Open questions at the time
    • ATM phosphorylation site on TIF-IA or p62 not mapped
    • Whether nuclear TIF-IA drives senescence phenotypes through Pol I activity or other mechanisms unclear
    • Not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how RRN3's DNA-binding, Pol I-bridging, and newly discovered mRNA-regulatory functions are coordinated; how the multisite phosphorylation code is integrated at the structural level; and whether non-canonical nucleoplasmic functions of RRN3 operate independently of its role in Pol I transcription.
  • No high-resolution ternary complex structure with promoter DNA and SL1
  • Phosphorylation code integration across kinases not modeled structurally
  • Non-canonical mRNA regulatory mechanism needs independent replication and full target identification

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 1
Localization
GO:0005654 nucleoplasm 3 GO:0005730 nucleolus 3 GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 8 R-HSA-162582 Signal Transduction 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-9612973 Autophagy 1
Partners
CSNK2A1CTDP1POLR1ARPA43SQSTM1TAF1ATAF1B
Complex memberships
Pol I–Rrn3 initiation complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 TIF-IA (RRN3 mammalian homolog) is a growth-dependent transcription initiation factor that co-purifies with RNA polymerase I and is required for accurate and efficient rRNA transcription initiation in vitro; its amount or activity is absent in quiescent cells. Biochemical fractionation, in vitro transcription reconstitution Nucleic acids research High 4070001
1990 TIF-IA physically associates with RNA polymerase I, converting it into a transcriptionally active holoenzyme capable of specific rDNA promoter initiation; dephosphorylation of Pol I abolishes in vitro transcription initiation without affecting non-specific polymerizing activity. Biochemical co-purification, in vitro transcription, phosphatase treatment The EMBO journal High 2390974
1993 TIF-IA is a 75 kDa monomeric polypeptide that interacts with RNA polymerase I; preinitiation complexes can form without TIF-IA but cannot initiate transcription (form first phosphodiester bonds) without it; after initiation, TIF-IA is liberated from the initiation complex. Purification, reconstituted transcription system with purified factors, template commitment assays Molecular and cellular biology High 8413268
1996 Yeast Rrn3p is an essential RNA polymerase I transcription factor that interacts directly with Pol I independently of DNA template, stimulating Pol I recruitment to the promoter and formation of a Sarkosyl-resistant preinitiation complex; Rrn3p is not stably part of the preinitiation complex through multiple rounds of transcription. Immunoaffinity purification, in vitro transcription complementation, template commitment assays, single-round transcription with Sarkosyl The EMBO journal High 8670901
1997 Yeast Cbf5p genetically interacts with RRN3; RRN3 was identified as a multicopy suppressor of cbf5-1 temperature-sensitive mutant deficient in rRNA biosynthesis. Genetic suppressor screen, multicopy suppression Molecular and cellular biology Medium 9315678
2000 Yeast Rrn3 interacts with Pol I subunit A43 to form a transcriptionally competent Pol I-Rrn3 complex; conditional mutations in A43 disrupt this complex, the two proteins form a stable complex when co-expressed in E. coli, overexpression of Rrn3 suppresses A43 mutant phenotype, and A43/Rrn3 mutants show synthetic lethality. Rrn3 also contacts the C-terminus of Rrn6 (core factor subunit), bridging Pol I to the core factor at the rDNA promoter. Genetic suppression, synthetic lethality, co-expression in E. coli, affinity chromatography, two-hybrid screen, immunoelectron microscopy The EMBO journal High 11032814
2000 TIF-IA is the mammalian homolog of yeast Rrn3p; recombinant TIF-IA interacts with Pol I in the absence of template DNA, augments Pol I transcription in vivo, and rescues transcription in extracts from growth-arrested cells in vitro. Molecular cloning, sequence homology, in vitro transcription complementation, in vivo overexpression EMBO reports High 11265758
2000 Human Rrn3 can rescue a yeast strain with disrupted RRN3 gene in vivo; a conserved point mutation compromises function in both yeast and human, confirming functional conservation. Yeast complementation assay, point mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 10758157
2002 TIF-IA interacts with Pol I subunits RPA43 and PAF67 via amino acids 512–609, and with TIF-IB/SL1 subunits TAF(I)95 and TAF(I)68 via a conserved LARAK motif (amino acids 411–415); nutrient starvation, density arrest, and protein synthesis inhibitors inactivate TIF-IA and impair its association with Pol I. Deletion mutant mapping, co-immunoprecipitation, in vitro interaction assays EMBO reports High 12393749
2002 Phosphorylation state of Rrn3 regulates its interaction with the rpa43 subunit of RNA polymerase I; cycloheximide inhibits Rrn3 phosphorylation and causes dissociation from Pol I; dephosphorylated Rrn3 or bacterially-expressed Rrn3 (unphosphorylated) cannot restore transcription or interact with rpa43 in vitro. Co-immunoprecipitation in vivo, in vitro interaction assays with Sf9-expressed vs. E. coli-expressed Rrn3, transcription complementation The Journal of biological chemistry High 12015311
2003 Mammalian Rrn3 becomes inactivated (unable to form stable complex with Pol I) during the course of transcription; Rrn3 functions stoichiometrically rather than catalytically in rDNA transcription. In vitro transcription reactions, reuse assay of Rrn3 isolated post-transcription, co-immunoprecipitation The Journal of biological chemistry Medium 12646563
2003 ERK and RSK kinases phosphorylate TIF-IA at Ser633 and Ser649; replacement of Ser649 with alanine inactivates TIF-IA, inhibits pre-rRNA synthesis, and retards cell growth, linking growth factor MAPK signaling to rDNA transcription. Phosphopeptide mapping, site-directed mutagenesis, in vivo rRNA synthesis assay, cell growth assay, kinase inhibitor (PD98059) treatment Molecular cell High 12620228
2004 mTOR signaling regulates Pol I transcription through TIF-IA; rapamycin-mediated mTOR inhibition causes hypophosphorylation of Ser44 (activating site) and hyperphosphorylation of Ser199 (inactivating site) of TIF-IA, impairs initiation complex formation, and causes TIF-IA translocation from nucleus to cytoplasm. Rapamycin treatment, phosphomutant analysis, transcription initiation complex assays, subcellular fractionation/localization Genes & development High 15004009
2005 Genetic inactivation of TIF-IA leads to nucleolar disruption, cell cycle arrest, upregulation of p53 via increased binding of ribosomal protein L11 to MDM2 (reducing MDM2-p53 interaction), and p53-mediated apoptosis; RNAi-mediated loss of p53 rescues proliferation arrest. Homologous recombination knockout, Cre-mediated depletion in MEFs, co-immunoprecipitation (L11-MDM2), RNAi rescue, nucleolar morphology Molecular cell High 15989966
2005 JNK2 phosphorylates TIF-IA at Thr200 upon stress, impairing TIF-IA interaction with both Pol I and TIF-IB/SL1, thereby abrogating initiation complex formation and causing TIF-IA translocation from nucleolus to nucleoplasm; Thr200Val substitution or Jnk2 knockout prevents inactivation. Kinase assay, site-directed mutagenesis, co-immunoprecipitation, subcellular localization, Jnk2 knockout cells, initiation complex assay Genes & development High 15805466
2007 In Drosophila, TIF-IA (RRN3 ortholog) is required for rRNA synthesis and cell growth in vivo; TOR pathway regulates TIF-IA recruitment to rDNA, and TIF-IA overexpression can maintain rRNA transcription when TOR activity is reduced. Drosophila genetics (Tif-IA mutants), ChIP, epistasis with TOR pathway, overexpression rescue The Journal of cell biology High 18086911
2007 Pol I subunits Rpa34 and Rpa49 (yeast) regulate both the recruitment of Rrn3 to the rDNA promoter and its release during elongation; rpa49 mutants partially impair Rrn3 promoter recruitment (bypassed by N-terminal deletion of Rpa43) and strongly reduce release of Rrn3 during elongation. Yeast genetics, two-hybrid assay, ChIP, polymerase occupancy assay, drug sensitivity assays Molecular and cellular biology High 18086878
2008 CK2 phosphorylates TIF-IA at Ser170/172, triggering release of TIF-IA from the RPA43 subunit of Pol I after transcription initiation; blocking this phosphorylation (or tethering TIF-IA to RPA43) inhibits rDNA transcription elongation. FCP1 phosphatase dephosphorylates Ser170/172 to allow TIF-IA reassociation with Pol I for new transcription rounds. In vitro kinase assay, site-directed mutagenesis, FRAP, ChIP, co-immunoprecipitation, covalent tethering experiment Molecular and cellular biology High 18559419
2008 Rrn3 must be present during committed template complex formation for transcription to occur; the functional preinitiation complex (assembled with active Rrn3) is approximately 5-fold more resistant to heparin than the non-functional complex assembled without Rrn3, though Pol I can be recruited to template even without active Rrn3. Novel template recruitment assay (ChIP-like), heparin resistance assay, in vitro transcription Gene expression Medium 18590050
2009 TIF-IA rapidly shuttles between cytoplasm, nucleoplasm, and nucleolus with mean nucleolar residence time of ~30 s; upon ribotoxic stress (JNK2 activation), TIF-IA is released from nucleoli with a half-time of ~24 min, slower than its normal exchange rate, identifying JNK2 activation as the rate-limiting step for stress-induced relocalization. Live-cell fluorescence microscopy (FRAP), kinetic modeling, GFP-tagging, subcellular compartment analysis Biochimica et biophysica acta Medium 19450626
2011 Crystal structure of Rrn3 reveals a unique HEAT repeat fold with a surface serine patch; phosphorylation of this serine patch represses human Pol I transcription; phospho-mimetic mutation prevents Rrn3 binding to Pol I in vitro, reduces cell growth and Pol I gene occupancy in vivo. Cross-linking shows Rrn3 binds between Pol I subcomplexes AC40/19 and A14/43. X-ray crystallography, cross-linking mass spectrometry, mutagenesis, in vitro binding assay, ChIP, cell growth assay Genes & development High 21940764
2013 Rrn3 is a DNA-binding protein; a domain (amino acids 382-400) with similarity to the HSF2 DNA-binding domain is essential for DNA binding; randomization or deletion of this domain abolishes DNA binding and abolishes rDNA transcription in vitro and yeast complementation, while preserving interactions with rpa43 and SL1. DNA binding assay, site-directed mutagenesis, in vitro transcription, yeast complementation, co-immunoprecipitation The Journal of biological chemistry High 23393135
2013 Activated Akt enhances rRNA synthesis by phosphorylating CK2α, which in turn phosphorylates TIF-IA; activated Akt also stabilizes TIF-IA protein, induces its translocation to the nucleolus, and enhances its interaction with Pol I. Co-immunoprecipitation, subcellular fractionation, kinase assays, pharmacological inhibitors (AZD8055, rapamycin), in vivo transcription assay Proceedings of the National Academy of Sciences of the United States of America Medium 24297901
2014 A 22 amino acid peptide within rpa43 is necessary and sufficient to mediate the rpa43-Rrn3 interaction interface; this peptide inhibits rDNA transcription in vitro and in cells, and blocks Pol I transcription and cell division. In silico analysis, in vitro transcription inhibition assay, cell transduction with TAT-coupled peptide, cell proliferation assay Molecular cancer research Medium 25033839
2016 Cryo-EM structure of the Pol I-Rrn3 complex at 4.8 Å resolution reveals how Rrn3 binding converts an inactive Pol I dimer into an initiation-competent monomeric complex. Cryo-electron microscopy structural determination Nature communications High 27418309
2016 Heat shock inactivates TIF-IA by inhibiting CK2-dependent phosphorylation at Ser170/172; this is accompanied by upregulation of lncRNA PAPAS, which interacts with CHD4 (NuRD ATPase subunit) to deacetylate histones and reposition the promoter nucleosome to repress rDNA transcription. In vivo phosphorylation assay, RNAi knockdown, RNA-protein interaction assay, nucleosome positioning assay, ChIP Nucleic acids research High 27257073
2016 LKB1 kinase activity promotes TIF-IA nuclear accumulation; in the presence of wild-type LKB1 (but not a kinase-dead mutant), TIF-IA quickly accumulates in the nucleus, maintaining pre-rRNA synthesis under AICAR-induced stress conditions. Cellular fractionation, wild-type vs. kinase-dead LKB1 expression, RNAi knockdown, TIF-IA phosphomutant analysis Oncotarget Medium 26506235
2017 ChIP-Seq after conditional inactivation of Rrn3 shows that preinitiation complex formation at rDNA is driven by UBF (UBTF) independently of transcription; loss of Rrn3 causes loss of Pol I from rDNA but an Enhancer Boundary Complex (CTCF/Cohesin) is stably maintained. High-resolution ChIP-Seq, conditional gene inactivation PLoS genetics Medium 28715449
2018 TIF-IA degradation by specific NF-κB stress stimuli is dependent on UBF/p14ARF and Ser44 of TIF-IA, and precedes NF-κB activation; blocking TIF-IA degradation blocks stress effects on nucleolar size and NF-κB signaling, defining a TIF-IA-NF-κB nucleolar stress response pathway. CDK4 inhibition mimics TIF-IA degradation. RNAi knockdown, TIF-IA mutant (S44) analysis, CDK4 inhibitor treatment, co-immunoprecipitation, NF-κB reporter assay, ex vivo tissue analysis Nucleic acids research Medium 29873780
2025 Under nutrient deprivation, phosphorylation of RRN3 at Ser199 causes its translocation from nucleolus to nuclear plasma, where it regulates alternative polyadenylation (APA) of autophagy-related mRNAs (e.g., OPTN), enhancing their stability and promoting autophagy. Long-read RNA sequencing, PAR-CLIP, cellular fractionation, phosphomutant analysis, in vivo tumor xenograft Cell death & disease Medium 41271632
2026 In proliferating cells, TIF-IA binds to the cargo receptor p62 (SQSTM1); ATM activation during senescence disrupts this interaction, causing TIF-IA accumulation in the nucleus/nucleolus, which is essential for nucleolar phenotypic changes, SASP establishment, and increased ROS levels in senescence. Co-immunoprecipitation, ATM inhibition, multiple senescence models (OIS and TIS), mouse models, ROS measurement Aging cell Medium 41466483
2026 EGR1 activates RRN3 gene transcription by binding to the RRN3 promoter, and also directly interacts with Pol I transcription machinery components via its DNA-binding domain to enhance their recruitment to the rDNA promoter. ChIP, promoter reporter assay, co-immunoprecipitation, RNAi knockdown, in vivo tumor model Communications biology Medium 41507426

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes & development 382 15004009
2005 Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest, and p53-mediated apoptosis. Molecular cell 219 15989966
2003 ERK-dependent phosphorylation of the transcription initiation factor TIF-IA is required for RNA polymerase I transcription and cell growth. Molecular cell 219 12620228
2005 The nucleolus as a stress sensor: JNK2 inactivates the transcription factor TIF-IA and down-regulates rRNA synthesis. Genes & development 175 15805466
2000 The recruitment of RNA polymerase I on rDNA is mediated by the interaction of the A43 subunit with Rrn3. The EMBO journal 146 11032814
1990 A growth-dependent transcription initiation factor (TIF-IA) interacting with RNA polymerase I regulates mouse ribosomal RNA synthesis. The EMBO journal 114 2390974
2000 TIF-IA, the factor mediating growth-dependent control of ribosomal RNA synthesis, is the mammalian homolog of yeast Rrn3p. EMBO reports 113 11265758
1996 RRN3 gene of Saccharomyces cerevisiae encodes an essential RNA polymerase I transcription factor which interacts with the polymerase independently of DNA template. The EMBO journal 108 8670901
1985 Growth-dependent regulation of rRNA synthesis is mediated by a transcription initiation factor (TIF-IA). Nucleic acids research 94 4070001
1997 The yeast nucleolar protein Cbf5p is involved in rRNA biosynthesis and interacts genetically with the RNA polymerase I transcription factor RRN3. Molecular and cellular biology 92 9315678
2000 RNA polymerase I transcription factor Rrn3 is functionally conserved between yeast and human. Proceedings of the National Academy of Sciences of the United States of America 91 10758157
2011 Molecular basis of Rrn3-regulated RNA polymerase I initiation and cell growth. Genes & development 88 21940764
2007 Drosophila TIF-IA is required for ribosome synthesis and cell growth and is regulated by the TOR pathway. The Journal of cell biology 81 18086911
2002 Multiple interactions between RNA polymerase I, TIF-IA and TAF(I) subunits regulate preinitiation complex assembly at the ribosomal gene promoter. EMBO reports 81 12393749
2002 Rrn3 phosphorylation is a regulatory checkpoint for ribosome biogenesis. The Journal of biological chemistry 75 12015311
2007 Two RNA polymerase I subunits control the binding and release of Rrn3 during transcription. Molecular and cellular biology 71 18086878
1993 Function of the growth-regulated transcription initiation factor TIF-IA in initiation complex formation at the murine ribosomal gene promoter. Molecular and cellular biology 70 8413268
2008 Phosphorylation by casein kinase 2 facilitates rRNA gene transcription by promoting dissociation of TIF-IA from elongating RNA polymerase I. Molecular and cellular biology 66 18559419
2013 Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA. Proceedings of the National Academy of Sciences of the United States of America 65 24297901
2017 A unique enhancer boundary complex on the mouse ribosomal RNA genes persists after loss of Rrn3 or UBF and the inactivation of RNA polymerase I transcription. PLoS genetics 63 28715449
2016 Heat shock represses rRNA synthesis by inactivation of TIF-IA and lncRNA-dependent changes in nucleosome positioning. Nucleic acids research 55 27257073
2016 RNA polymerase I-Rrn3 complex at 4.8 Å resolution. Nature communications 54 27418309
2013 DNA binding by the ribosomal DNA transcription factor rrn3 is essential for ribosomal DNA transcription. The Journal of biological chemistry 33 23393135
2003 Rrn3 becomes inactivated in the process of ribosomal DNA transcription. The Journal of biological chemistry 29 12646563
2018 Identification of a novel TIF-IA-NF-κB nucleolar stress response pathway. Nucleic acids research 22 29873780
2016 TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis. Biochimica et biophysica acta 22 27641688
2014 TIF-IA-dependent regulation of ribosome synthesis in drosophila muscle is required to maintain systemic insulin signaling and larval growth. PLoS genetics 22 25356674
2014 Selective inhibition of rDNA transcription by a small-molecule peptide that targets the interface between RNA polymerase I and Rrn3. Molecular cancer research : MCR 20 25033839
2008 Mammalian Rrn3 is required for the formation of a transcription competent preinitiation complex containing RNA polymerase I. Gene expression 20 18590050
2007 Biased exonization of transposed elements in duplicated genes: A lesson from the TIF-IA gene. BMC molecular biology 19 18047649
2009 Dynamic subcellular partitioning of the nucleolar transcription factor TIF-IA under ribotoxic stress. Biochimica et biophysica acta 13 19450626
2016 LKB1 promotes cell survival by modulating TIF-IA-mediated pre-ribosomal RNA synthesis under uridine downregulated conditions. Oncotarget 9 26506235
2022 Rrn3 gene knockout affects ethanol-induced locomotion in adult heterozygous zebrafish. Psychopharmacology 4 35006303
2015 TIF-IA and Ebp1 regulate RNA synthesis in T cells. Blood 2 25883228
2005 The association of TIF-IA and polymerase I mediates promoter recruitment and regulation of ribosomal RNA transcription in Acanthamoeba castellanii. Gene expression 1 16358415
2026 Loss of p62 Binding Allows TIF-IA Accumulation in Senescence, Which Promotes Phenotypic Changes to Nucleoli and the Senescence Associated Secretory Phenotype. Aging cell 0 41466483
2026 Early growth response 1 promotes RNA polymerase I-directed transcription and cancer growth by activating RRN3 expression. Communications biology 0 41507426
2025 NSH76: a selective inhibitor of RRN3 and RNA polymerase I transcription with potential for cancer therapy. Journal of translational medicine 0 41116164
2025 Nutrient stress diverts RRN3 from rRNA transcription to alternative polyadenylation of autophagy mRNAs in ovarian cancer. Cell death & disease 0 41271632