Affinage

CDC73

Parafibromin · UniProt Q6P1J9

Length
531 aa
Mass
60.6 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC73 (parafibromin) is a scaffolding subunit of the PAF1 complex that couples RNA polymerase II transcription elongation to chromatin modification, mRNA 3′ end processing, and developmental signaling. Within the PAF1 complex, CDC73 associates with PAF1, LEO1, CTR9, and Spt6, and recruits the histone methyltransferase SUV39H1 to repress cyclin D1 and c-myc via H3K9 methylation, while also promoting H2B-K120 monoubiquitination through interaction with the RNF20/RNF40 E3 ligase (PMID:15632063, PMID:19906718, PMID:22021426, PMID:36928138). CDC73 functions as a phosphorylation-regulated molecular switch: SHP2-mediated tyrosine dephosphorylation enables binding to β-catenin, Gli proteins, and NICD, converting CDC73 from a transcriptional repressor into a direct nuclear effector of Wnt, Hedgehog, and Notch signaling, whereas phosphorylation by PTK6 attenuates these activities (PMID:16630820, PMID:21726809, PMID:27650679). Beyond transcription, CDC73 associates with CPSF/CstF to direct mRNA 3′ end maturation, controls replication-dependent histone mRNA processing, promotes homologous recombination repair through chromatin decondensation at DNA damage sites, and destabilizes cytoplasmic p53 mRNA via an eEF1Bγ/hSki8-containing complex (PMID:19136632, PMID:19908240, PMID:27462432, PMID:25388829).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2005 High

    Identifying CDC73 as a bona fide PAF1 complex subunit resolved how a tumor suppressor gene product interfaces with the RNA Pol II transcription elongation machinery.

    Evidence Mass spectrometry of purified parafibromin complexes and reciprocal co-immunoprecipitation with PAF1, LEO1, CTR9, and phospho-Pol II CTD forms in human cells, replicated across two independent labs

    PMID:15632063 PMID:15923622

    Open questions at the time
    • Stoichiometry of human PAF1 complex not determined
    • Which CDC73 surfaces directly contact each subunit was unknown
  2. 2005 Medium

    Demonstrating that overexpressed wild-type but not mutant parafibromin represses cyclin D1 and inhibits proliferation established CDC73's tumor-suppressive mechanism at a defined target gene.

    Evidence Transient overexpression with L64P mutant control, cyclin D1 Western blot, and cell proliferation assay

    PMID:15580289

    Open questions at the time
    • Overexpression system; endogenous loss-of-function validation of cyclin D1 regulation was lacking
    • Mechanism of promoter-level repression not yet dissected
  3. 2005 High

    Mapping a nuclear localization signal in parafibromin explained why clinically observed truncating mutations cause loss of function by mislocalizing the protein.

    Evidence GFP-tagged mutagenesis with confocal microscopy and nuclear/cytoplasmic fractionation, confirmed independently

    PMID:16116486 PMID:16964291

    Open questions at the time
    • Whether cytoplasmic parafibromin retains any function was unclear
  4. 2006 High

    Showing that parafibromin directly binds β-catenin and is required for Wnt nuclear transduction repositioned CDC73 from a general transcription factor to a signal-specific transcriptional effector.

    Evidence Drosophila genetic epistasis with Hyrax, direct binding assays, and co-immunoprecipitation with β-catenin in mammalian cells

    PMID:16630820

    Open questions at the time
    • Whether binding is constitutive or signal-regulated was not known
    • Structural basis of β-catenin–parafibromin interface unresolved
  5. 2007 High

    Linking nuclear localization to both PAF1 complex assembly and proapoptotic activity demonstrated that CDC73's tumor suppression requires its nuclear role rather than cytoplasmic functions.

    Evidence NLS mutagenesis with co-immunoprecipitation for PAF1/LEO1 and apoptosis assays upon RNAi knockdown

    PMID:17314275

    Open questions at the time
    • Downstream apoptotic pathway not fully delineated
    • Whether a cytoplasmic pool has independent pro-survival functions was unresolved
  6. 2008 High

    ChIP-based identification of c-myc as a direct PAF1-complex-occupied target gene, combined with epistatic rescue by c-myc knockdown, provided the first complete transcriptional circuit linking CDC73 loss to oncogene derepression and proliferation.

    Evidence ChIP for PAF1 complex subunits at the c-myc promoter; RNAi epistasis showing c-myc knockdown blocks parafibromin-depletion-induced proliferation

    PMID:18987311

    Open questions at the time
    • Mechanism distinguishing repression at c-myc from activation at Wnt targets not clarified
  7. 2008 High

    Conditional knockout in mice proved CDC73 is essential for embryonic viability and identified downstream growth/survival gene targets (Igf axis, Hmga genes) by ChIP, moving from cell-line studies to organismal requirement.

    Evidence Conditional Hrpt2 knockout mouse with embryonic lethality at E6.5; cDNA microarray and ChIP in MEFs

    PMID:18212049

    Open questions at the time
    • Tissue-specific requirements beyond early embryogenesis incompletely mapped
    • Relative contribution of individual target genes to lethality unknown
  8. 2009 High

    Discovery that CDC73 physically associates with CPSF/CstF and is required for mRNA 3′ end processing in vitro expanded its function beyond transcription elongation to co-transcriptional RNA maturation.

    Evidence Co-immunoprecipitation, immunodepletion abolishing in vitro 3′ processing, siRNA with ChIP showing loss of CPSF/CstF at a target locus

    PMID:19136632

    Open questions at the time
    • Whether CDC73 directly contacts CPSF/CstF or acts via PAF1 complex bridging was not resolved
    • Genome-wide scope of 3′ processing dependency unknown
  9. 2009 High

    Identification of SUV39H1 as a CDC73-recruited histone methyltransferase that deposits H3K9me at the cyclin D1 locus provided a direct epigenetic mechanism for CDC73-mediated gene repression distinct from H3K4 methylation.

    Evidence Co-immunoprecipitation with domain mapping; ChIP showing H3K9 methylation at cyclin D1 promoter/coding regions dependent on parafibromin

    PMID:19906718

    Open questions at the time
    • Whether SUV39H1 recruitment is gene-specific or genome-wide was unknown
    • H3K9me reader proteins downstream were not identified
  10. 2009 Medium

    Binding of parafibromin to all three Gli proteins and Drosophila Ci placed CDC73 as a shared nuclear effector of both Wnt and Hedgehog signaling pathways.

    Evidence Drosophila genetic epistasis; co-immunoprecipitation with Gli1/2/3; RNAi reducing Gli transcriptional activity

    PMID:19368795

    Open questions at the time
    • Whether Wnt and Hedgehog inputs compete for CDC73 binding was unresolved
    • In vivo mammalian Hedgehog phenotype of CDC73 loss not tested
  11. 2010 Medium

    Mapping a minimal 105-aa Cdc73 region sufficient for Ctr9 binding, nuclear localization, and suppression of gross chromosomal rearrangements linked PAF1 complex integrity to genome stability through telomere maintenance.

    Evidence Yeast GCR assay, deletion analysis, co-immunoprecipitation with Ctr9, telomere length and silencing assays

    PMID:29320491

    Open questions at the time
    • Mechanistic link between telomere dysfunction and GCR was correlative
    • Whether mammalian CDC73 loss also causes telomere defects was not tested
  12. 2011 High

    Demonstrating that SHP2-mediated tyrosine dephosphorylation of parafibromin switches it from a transcriptional repressor to a β-catenin-dependent transactivator provided the key regulatory logic explaining CDC73's dual tumor suppressor/oncogene behavior.

    Evidence In vitro SHP2 phosphatase assay; co-immunoprecipitation showing phosphorylation-dependent β-catenin binding; reporter assays

    PMID:21726809

    Open questions at the time
    • Tyrosine residue(s) phosphorylated on CDC73 not identified
    • Kinase responsible for CDC73 tyrosine phosphorylation was unknown at this point
  13. 2011 High

    Showing that CDC73 interacts with the RNF20/RNF40 E3 ligase and is required for H2B-K120 monoubiquitination in cells and tumors established a second chromatin modification axis controlled by CDC73, distinct from H3K9 methylation.

    Evidence Yeast two-hybrid, co-immunoprecipitation, siRNA, immunohistochemistry of CDC73-mutant parathyroid tumors

    PMID:22021426

    Open questions at the time
    • Whether CDC73 stimulates RNF20/RNF40 enzymatic activity or merely recruits it was unclear
    • Genome-wide pattern of H2Bub1 loss upon CDC73 mutation not mapped
  14. 2014 High

    Discovery that cytoplasmic parafibromin binds mature p53 mRNA via an eEF1Bγ/hSki8 complex and promotes its degradation revealed a post-transcriptional, non-PAF1-complex function that explains how cytoplasmic CDC73 can be oncogenic.

    Evidence RNA immunoprecipitation identifying p53 mRNA; co-immunoprecipitation with eEF1Bγ and hSki8; mRNA stability assays; K34Q cancer mutant with enhanced p53 mRNA binding

    PMID:25388829

    Open questions at the time
    • Whether other mRNAs are similarly regulated by cytoplasmic CDC73 was not addressed
    • Structural basis of CDC73–mRNA interaction unknown
  15. 2015 Medium

    A genome-wide screen placing CDC73 in homologous recombination repair through chromatin decondensation at damage sites broadened CDC73's roles beyond transcription to DNA damage response.

    Evidence Genome-wide siRNA screen; RAD51/RPA foci assays; HR reporter assay; co-immunoprecipitation with SCF/Cullin and INO80/NuA4 components

    PMID:27462432

    Open questions at the time
    • Whether the HR function depends on PAF1 complex or is CDC73-autonomous was not resolved
    • Direct DNA-damage-site recruitment mechanism unclear
  16. 2015 High

    Confirming parafibromin as a direct SHP2 substrate using LEOPARD syndrome mutants with reduced phosphatase activity validated the phosphorylation switch model with disease-relevant mutations.

    Evidence In vitro phosphatase assay with panel of LEOPARD-associated SHP2 mutants and tyrosine-phosphorylated parafibromin substrate

    PMID:26742426

    Open questions at the time
    • In vivo relevance in LEOPARD syndrome patients not tested
    • Which tyrosine residues on CDC73 are dephosphorylated still unidentified
  17. 2016 High

    Showing that dephosphorylated parafibromin competitively binds β-catenin, Gli1, and NICD in a mutually exclusive manner, with PTK6 as the opposing kinase to SHP2, unified Wnt, Hedgehog, and Notch nuclear effector functions under a single phospho-switch.

    Evidence Co-immunoprecipitation with competitive binding; reporter assays; conditional mouse intestinal knockout with epithelial disorganization

    PMID:27650679

    Open questions at the time
    • Structural basis for mutually exclusive binding not determined
    • In vivo consequences for Hedgehog and Notch targets in the intestine not individually dissected
  18. 2017 High

    The 1.02 Å crystal structure of the CDC73 N-terminal domain revealed a novel fold and explained how HPT-JT-associated missense mutations destabilize the protein, providing the first structural framework for interpreting clinical mutations.

    Evidence X-ray crystallography at atomic resolution; limited proteolysis; thermostability assays of pathogenic mutants

    PMID:29142233

    Open questions at the time
    • Structure of the C-terminal PAF1-complex-interacting domain not solved
    • No co-crystal with any binding partner
  19. 2022 Medium

    Identification of UBR5-mediated polyubiquitination at specific lysines (K243/K247/K257) as a Ser465-phosphorylation-dependent degradation mechanism established how CDC73 protein levels are post-translationally controlled.

    Evidence Ubiquitination assays with site-directed mutagenesis; co-immunoprecipitation; in vivo xenograft in triple-negative breast cancer

    PMID:35551175

    Open questions at the time
    • Kinase responsible for Ser465 phosphorylation not identified
    • Whether UBR5-mediated degradation is context-dependent across tissues not established
  20. 2023 High

    Direct cross-linking of Cdc73 to the Spt6 tSH2 domain and to Rpb1 in vivo, combined with rapid Spt6 depletion causing genome-wide loss of Paf1C from chromatin, established Spt6 as a critical bridge anchoring the PAF1 complex to elongating Pol II.

    Evidence Site-specific protein cross-linking in yeast; in vitro binding assay; auxin-inducible degron depletion with ChIP-seq

    PMID:36928138

    Open questions at the time
    • Whether the Spt6–Cdc73 interaction is conserved in metazoans not tested
    • No structure of the Spt6–Cdc73–Pol II ternary complex

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of specific tyrosine residues phosphorylated on CDC73 that govern the repressor/activator switch, the structural basis for competitive β-catenin/Gli/NICD binding, and the full-length structure of CDC73 in complex with PAF1 complex subunits.
  • Phosphorylated tyrosine residues not mapped
  • No full-length CDC73 structure or PAF1 complex co-structure
  • Genome-wide target specificity of repression vs. activation functions not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0060090 molecular adaptor activity 4 GO:0042393 histone binding 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 4 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-73894 DNA Repair 1
Partners
CTNNB1CTR9LEO1PAF1RNF20RNF40SPT6SUV39H1
Complex memberships
CPSF/CstF 3' processing complexPAF1 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Parafibromin (CDC73) is a component of the human PAF1 complex, physically associating with PAF1, LEO1, and CTR9 homologs, and co-purifies with non-phosphorylated, Ser2-phosphorylated, and Ser5-phosphorylated forms of the RNA polymerase II large subunit. Cotransfection data suggest parafibromin can interact with a histone methyltransferase complex that methylates histone H3 on lysine 4. Cellular purification of parafibromin followed by mass spectrometry identification of associated proteins; co-immunoprecipitation; immunofluorescence; cotransfection assays Molecular and cellular biology High 15632063
2005 Parafibromin physically interacts with human orthologs of yeast Paf1 complex components (PAF1, LEO1, CTR9) involved in transcription elongation and 3' end processing, and associates with RNA polymerase II large subunit phosphorylated on Ser5 or Ser2 of its CTD. These interactions depend on a C-terminal domain of parafibromin deleted in ~80% of clinically relevant mutations. RNAi-induced downregulation of parafibromin promotes entry into S phase. Co-immunoprecipitation; RNAi knockdown with cell cycle analysis Molecular and cellular biology High 15923622
2006 Drosophila Hyrax (parafibromin ortholog) and human Parafibromin are required for nuclear transduction of the Wnt/Wg signal and bind directly to the C-terminal region of beta-catenin/Armadillo. The transactivation potential of Parafibromin/Hyrax depends on recruitment of Pygopus to beta-catenin/Armadillo, identifying the PAF1 complex as a direct nuclear effector of Wnt signaling. Genetic epistasis in Drosophila; direct binding assays; co-immunoprecipitation Cell High 16630820
2005 Transient overexpression of wild-type parafibromin, but not its Leu64Pro missense mutant, inhibits cell proliferation and blocks expression of cyclin D1, a key cell cycle regulator, demonstrating a functional role for parafibromin in repressing cyclin D1. Transient overexpression; cell proliferation assay; Western blot for cyclin D1 Oncogene Medium 15580289
2006 Parafibromin contains a functional monopartite nuclear localization signal (NLS) at residues 136-139 (KKXR) that is evolutionarily conserved and critical for nuclear localization; deletion or mutation of this NLS abolishes nuclear targeting. Site-directed mutagenesis; confocal fluorescence microscopy of GFP-tagged constructs; Western blot of nuclear/cytoplasmic fractions Oncogene High 16964291
2005 A functional bipartite nuclear localization signal (NLS) in parafibromin was identified at residues 125-139 (KRAADEVLAEAKKPR); the C-terminal arm of this bipartite NLS plays the primary role in nuclear localization. Specific HRPT2 mutations that truncate parafibromin upstream of or within this NLS disrupt nuclear localization. Expression of GFP-tagged wild-type and mutant parafibromin; confocal fluorescence microscopy Oncogene High 16116486
2009 CDC73 (Cdc73/parafibromin) physically associates with the cleavage and polyadenylation specificity factor (CPSF) and cleavage stimulation factor (CstF) complexes required for mRNA 3' end maturation. Immunodepletion of the Cdc73-CPSF-CstF complex abolishes 3' mRNA processing in vitro. CDC73 siRNA leads to decreased INTS6 mRNA abundance and decreased CPSF/CstF association with the INTS6 locus. Co-immunoprecipitation; in vitro mRNA 3' processing assay with immunodepletion; siRNA knockdown; microarray; chromatin immunoprecipitation (ChIP) Proceedings of the National Academy of Sciences of the United States of America High 19136632
2008 Parafibromin inhibits cell proliferation and represses the c-myc proto-oncogene through both c-myc protein stabilization inhibition and promoter repression via the PAF1 complex. Chromatin immunoprecipitation demonstrates direct occupancy of the c-myc promoter by parafibromin and other PAF1 complex subunits. Knockdown of c-myc blocks the proliferative effect of parafibromin/Paf1 RNAi. RNAi knockdown; cell proliferation assay; ChIP; Western blot; reporter assay Proceedings of the National Academy of Sciences of the United States of America High 18987311
2009 Parafibromin interacts with the histone methyltransferase SUV39H1 via its central region (residues 128-227), recruits SUV39H1 to the promoter and coding regions of cyclin D1, and induces H3 K9 methylation (but not H3 K4 methylation) at the cyclin D1 locus, thereby repressing cyclin D1 expression. Co-immunoprecipitation; ChIP; RNAi knockdown; reporter assay; deletion mapping Nucleic acids research High 19906718
2011 CDC73 interacts with the E3 ubiquitin ligase ring finger proteins RNF20 and RNF40 (which form a heterodimer catalyzing monoubiquitination of histone H2B at K120). CDC73 binds to discrete but closely located residues on RNF20 and RNF40. Loss of nuclear CDC73 in vitro (by siRNA) or in CDC73-mutant parathyroid tumors significantly reduces H2B-K120 monoubiquitination, while H3-K4me3 remains unchanged. Yeast two-hybrid screen; co-immunoprecipitation; siRNA knockdown; immunohistochemistry of tumor tissue; Western blot for histone modifications Human molecular genetics High 22021426
2011 SHP2 phosphatase dephosphorylates parafibromin on tyrosine residues. Tyrosine dephosphorylation by SHP2 enables parafibromin to stably bind beta-catenin, thereby activating Wnt target genes including cyclin D1 and c-myc, overriding the parafibromin/SUV39H1-mediated transrepression. Thus, SHP2 governs the opposing tumor suppressor vs. oncogenic functions of parafibromin. In vitro phosphatase assay; co-immunoprecipitation; reporter assay; Western blot; cell-based functional assays Molecular cell High 21726809
2007 Nuclear localization of parafibromin is required for its proapoptotic activity. Mutation of both a dominant bipartite NLS and a secondary NLS in the NH2-terminal region nearly abolishes nuclear targeting, significantly impairs association with endogenous Paf1 and Leo1, and abolishes the ability of overexpressed parafibromin to induce apoptosis. Endogenous parafibromin knockdown by RNAi inhibits basal apoptosis and camptothecin-induced apoptosis. Site-directed mutagenesis; co-immunoprecipitation; confocal fluorescence microscopy; RNAi; apoptosis assays Molecular cancer research : MCR High 17314275
2008 Parafibromin interacts with muscle alpha-actinins (actinin-2 and actinin-3) but not non-muscle alpha-actinins, through its N-terminal region. Parafibromin can bundle/cross-link actin filaments in actin sedimentation assays. In differentiated myotubes, parafibromin co-localizes with actinins in the cytoplasm, whereas in proliferating myoblasts it is predominantly nuclear. Yeast two-hybrid; GST pull-down; co-immunoprecipitation; actin sedimentation assay; confocal microscopy Molecular cancer Medium 18687124
2008 Parafibromin, as a transcription factor associated with the PAF complex, directly regulates genes involved in cell growth and survival (H19, Igf1, Igf2, Igfbp4, Hmga1, Hmga2, Hmgcs2) as shown by ChIP. Conditional homozygous deletion of Hrpt2 in mice causes embryonic lethality by E6.5, apoptosis in embryonic fibroblasts, and cachexia/death in adults. Conditional knockout mouse; cDNA microarray; chromatin immunoprecipitation; semi-quantitative RT-PCR; MEF culture with Cre-mediated deletion Molecular and cellular biology High 18212049
2010 Parafibromin regulates 3' processing of replication-dependent histone mRNA. Downregulation of parafibromin by siRNA or in vivo CDC73 mutations leads to uncleaved histone mRNA with polyadenylated tails, demonstrating a posttranscriptional role in histone mRNA 3' end processing. siRNA knockdown; RNA analysis (RT-PCR, Northern); analysis of tumor samples with in vivo mutations Molecular carcinogenesis Medium 19908240
2016 Dephosphorylated parafibromin competitively interacts with beta-catenin and Gli1, potentiating transactivation of Wnt- and Hedgehog-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted Wnt- and Notch-target gene activation. Tyrosine dephosphorylation by SHP2 potentiates and phosphorylation by PTK6 kinase attenuates these functions. Acute parafibromin loss in mouse intestine disorganizes epithelial architecture. Co-immunoprecipitation; reporter assays; conditional mouse knockout; immunofluorescence; cell-based assays Nature communications High 27650679
2009 Parafibromin/Hyrax acts as a positive component of Hedgehog signaling by directly binding Region 1 (the Su(fu) interaction domain) in the N-terminus of all three Gli proteins and Ci. Parafibromin forms a complex with Gli1, Gli2, and Gli3. RNAi knockdown of Parafibromin in mammalian cells diminishes transcriptional activity of Gli1 and Gli2. Drosophila genetic epistasis; RNAi in cell culture; co-immunoprecipitation; reporter assay Mechanisms of development Medium 19368795
2014 Cytoplasmic parafibromin/hCdc73 physically associates with mature p53 mRNA in the cytoplasm and facilitates its degradation, thereby controlling p53-mediated apoptosis. Cytoplasmic hCdc73 interacts with eEF1Bγ and hSki8; this interaction is required to bind and destabilize p53 mRNA. A cancer-associated K34Q mutant shows enhanced p53 mRNA binding and reduces p53 expression. RNA immunoprecipitation (RIP); co-immunoprecipitation; mRNA stability assay; mutagenesis; cell viability assay Nature communications High 25388829
2018 YAP and TAZ transcriptional co-activator functions are inversely regulated by parafibromin's tyrosine phosphorylation state. Tyrosine-dephosphorylated parafibromin stimulates TAZ and beta-catenin cooperatively; tyrosine-phosphorylated parafibromin selectively activates YAP without interacting with beta-catenin. Co-immunoprecipitation; reporter assay; mutagenesis; cell-based functional assays iScience Medium 30227954
2015 CDC73 interacts with components of the SCF/Cullin and INO80/NuA4 chromatin-remodeling complexes to promote histone ubiquitination, and is required for local chromatin decondensation at sites of DNA damage to promote homologous recombination repair. This function is related to but independent of CDC73's role in transcriptional elongation. Genome-wide siRNA screen; co-immunoprecipitation; RAD51 foci assay; HR repair assay; RPA foci assay Cell discovery Medium 27462432
2019 CDC73 interacts with RNA polymerase II in a phospho-CTD (carboxy-terminal domain)-dependent manner and is required for high ATR signaling, R-loop formation, and activation of the G2 checkpoint after PNUTS-PP1 depletion. ATR, RNAPII, and CDC73 co-immunoprecipitate. Co-immunoprecipitation; siRNA knockdown; ATR signaling assays; R-loop detection; checkpoint assay Nucleic acids research Medium 30541148
2022 UBR5 (HECT-domain E3 ubiquitin ligase) polyubiquitinates CDC73 at Lys243, Lys247, and Lys257, leading to its proteasomal degradation. This ubiquitination depends on the non-phosphorylation state of CDC73 at Ser465. CDC73 acts as a molecular switch to modulate UBR5's pro-tumor activities in triple-negative breast cancer. Co-immunoprecipitation; ubiquitination assay; site-directed mutagenesis; Western blot; in vivo xenograft Cell death & disease Medium 35551175
2017 Crystal structure of the N-terminal domain of human CDC73 (residues 1-111, hCDC73-NTD) at 1.02 Å resolution reveals a novel protein fold with an extended hydrophobic groove. Most pathogenic HPT-JT-associated missense mutations disrupt folding of the hydrophobic core of hCDC73-NTD, while others (e.g., K34Q) reduce thermostability. X-ray crystallography; limited proteolysis; biochemical thermostability assays Scientific reports High 29142233
2015 LEOPARD syndrome-associated SHP2 mutants (Y279C, T468M, Q506P, Q510E) exhibit substantially reduced phosphatase activity toward tyrosine-phosphorylated parafibromin in an in vitro phosphatase assay, demonstrating parafibromin as a bona fide SHP2 substrate. In vitro phosphatase assay using tyrosine-phosphorylated parafibromin substrate; SHP2 mutant panel Biochemical and biophysical research communications High 26742426
2023 In yeast, Cdc73 directly interacts with the transcription elongation factor Spt6 (through Spt6's tandem SH2 domain) and with the largest subunit of RNA polymerase II. These interactions can be detected in vitro. Rapid depletion of Spt6 dissociates Paf1 from chromatin and alters Paf1C-dependent histone modifications genome-wide. A central 105 amino acid region of Cdc73 is necessary and sufficient for binding Ctr9 and nuclear localization, and suppresses genome instability. Site-specific protein cross-linking in yeast cells; in vitro binding assay; auxin-inducible degron (rapid depletion); ChIP-seq; deletion analysis Nucleic acids research High 36928138
2010 Parafibromin regulates the mRNA stability of CPEB1 (cytoplasmic polyadenylation element binding protein). Parafibromin occupies the CPEB1 locus as shown by ChIP. A genetic interaction between hyx/parafibromin and orb/CPEB was identified through Drosophila double heterozygote screens. Drosophila genetic screen; siRNA knockdown in mammalian cells; Western blot; chromatin immunoprecipitation Cell death and differentiation Medium 20339377
2010 A central 105 amino acid region of Cdc73 in yeast is necessary and sufficient for suppressing gross chromosomal rearrangements, binding to the Paf1 complex via Ctr9, and nuclear localization. Loss of Cdc73 causes increased telomere dysfunction and accumulation of chromosomal rearrangements, mediated by partial telomere dysfunction. GCR assay; deletion analysis; co-immunoprecipitation; telomere length analysis; telomeric silencing assay; whole genome sequencing PLoS genetics Medium 29320491
2010 Parafibromin deficiency (via L95P missense mutation) causes defective nucleolar localization and dominant-negative interference with endogenous parafibromin. The L95P mutant retains the ability to assemble with endogenous PAF1 complex components but is expressed at lower levels, is not rescued by proteasome inhibition, and enhances cell cycle progression and survival when transfected. Transfection; co-immunoprecipitation; confocal microscopy; cell cycle analysis; proteasome inhibitor treatment; flow cytometry Endocrine-related cancer Medium 20304979
2012 MicroRNA-155 (miR-155) directly targets the 3'-UTR of CDC73 mRNA, negatively regulating CDC73 expression. Ectopic miR-155 expression dramatically reduces CDC73 levels and enhances cell viability/reduces apoptosis; delivery of antagomir-155 increases CDC73 levels, decreases cell viability, and causes xenograft regression. miRNA overexpression/antagomir delivery; 3'-UTR reporter assay; Western blot; in vivo xenograft The Journal of biological chemistry Medium 23166327

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature genetics 509 12434154
2003 Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. The New England journal of medicine 398 14585940
2006 Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo. Cell 258 16630820
2003 HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. Journal of medical genetics 249 12960210
2005 The parafibromin tumor suppressor protein is part of a human Paf1 complex. Molecular and cellular biology 228 15632063
1995 Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. American journal of human genetics 187 7717405
2004 Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. The Journal of clinical endocrinology and metabolism 172 15531515
2004 Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 161 15475453
2006 Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias. The American journal of surgical pathology 154 16931959
2005 The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II. Molecular and cellular biology 154 15923622
2010 Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors. Human mutation 134 20052758
2005 Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene 122 15580289
2009 The tumor suppressor Cdc73 functionally associates with CPSF and CstF 3' mRNA processing factors. Proceedings of the National Academy of Sciences of the United States of America 114 19136632
2004 Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. The Journal of clinical endocrinology and metabolism 109 14715834
2012 Oncogenic microRNA-155 down-regulates tumor suppressor CDC73 and promotes oral squamous cell carcinoma cell proliferation: implications for cancer therapeutics. The Journal of biological chemistry 101 23166327
2007 Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? European journal of endocrinology 100 17468190
2008 Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. The Journal of clinical endocrinology and metabolism 96 19017757
2013 Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism 93 23293331
2011 SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver. Molecular cell 93 21726809
2006 HRPT2 gene alterations in ossifying fibroma of the jaws. Oral oncology 84 16458039
2006 Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours. Clinical endocrinology 82 16487440
2007 Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification. Endocrine-related cancer 80 17639063
2012 Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism. Hormones & cancer 77 22187299
2008 Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice. Molecular and cellular biology 75 18212049
2008 The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene. Proceedings of the National Academy of Sciences of the United States of America 75 18987311
2019 Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features. The American journal of surgical pathology 73 29324469
2017 CDC73-Related Disorders: Clinical Manifestations and Case Detection in Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism 73 29040582
2011 The tumor suppressor CDC73 interacts with the ring finger proteins RNF20 and RNF40 and is required for the maintenance of histone 2B monoubiquitination. Human molecular genetics 71 22021426
2006 Loss of parafibromin expression in a subset of parathyroid adenomas. Endocrine-related cancer 70 16728578
2010 The Arabidopsis Paf1c complex component CDC73 participates in the modification of FLOWERING LOCUS C chromatin. Plant physiology 69 20463090
2013 CDC73 mutational status and loss of parafibromin in the outcome of parathyroid cancer. Endocrine connections 68 24145611
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