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Showing CDC73 — PARAFIBROMIN is a alias.

CDC73

Parafibromin · UniProt Q6P1J9

Length
531 aa
Mass
60.6 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC73/parafibromin is a nuclear tumor suppressor that functions as a core subunit of the human PAF1 complex (with PAF1, LEO1, and CTR9), coupling RNA polymerase II transcription elongation to histone modification and 3' mRNA processing (PMID:15632063, PMID:15923622, PMID:19136632). Within this complex it controls transcription of genes governing proliferation and survival: it represses the oncogenes cyclin D1 and c-myc, occupying their promoters and recruiting the histone methyltransferase SUV39H1 to deposit repressive H3K9 methylation at cyclin D1 (PMID:18987311, PMID:19906718), and it interacts with the RNF20/RNF40 E3 ligase to promote H2B-K120 monoubiquitination (PMID:22021426). CDC73 also acts as a transcriptional co-activator at developmental signaling pathways, binding directly to beta-catenin (Wnt), Gli proteins (Hedgehog), and the Notch intracellular domain to drive target-gene expression (PMID:16630820, PMID:19368795, PMID:27650679). This dual repressor/activator output is governed by a tyrosine phosphorylation switch: SHP2-mediated dephosphorylation enables stable beta-catenin binding and an oncogenic activating program, whereas PTK6 phosphorylation attenuates it, with the phospho-state also dictating selective engagement of TAZ versus YAP (PMID:21726809, PMID:27650679, PMID:30227954). Nuclear function depends on an N-terminal nuclear localization signal and the structured N- and C-terminal domains, regions disrupted by the majority of HPT-JT and parathyroid carcinoma-associated mutations (PMID:16964291, PMID:29142233, PMID:32590342). Beyond transcription, CDC73 contributes to homologous recombination DNA repair through SCF/Cullin and INO80/NuA4 complexes (PMID:27462432) and exerts cytoplasmic post-transcriptional roles, including destabilization of p53 mRNA via eEF1Bgamma and hSki8 (PMID:25388829). Germline CDC73 mutations that disrupt the C-terminal domain predispose to parathyroid carcinoma (PMID:32590342).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2005 High

    Establishing that parafibromin is a bona fide subunit of the RNA Pol II-associated PAF1 complex placed an uncharacterized tumor suppressor into a defined transcriptional machinery and showed tumor mutations disrupt this association.

    Evidence Protein purification, mass spectrometry, reciprocal Co-IP and immunofluorescence in human cells; replicated with domain mapping and RNAi cell-cycle assays

    PMID:15632063 PMID:15923622

    Open questions at the time
    • Whether PAF1 complex assembly is sufficient for tumor suppression not resolved
    • Direct enzymatic activity of CDC73 within the complex undefined
  2. 2006 High

    Identification of direct binding to beta-catenin/Armadillo defined parafibromin as a nuclear effector of Wnt signaling, recasting the PAF1 complex as a transcriptional platform engaged by developmental pathways.

    Evidence Drosophila genetic epistasis, direct pulldown, transcriptional reporter assays, RNAi

    PMID:16630820

    Open questions at the time
    • How the same protein both represses and activates Wnt targets not yet reconciled at this stage
  3. 2005 High

    Mapping a functional nuclear localization signal explained why ~60% of clinical mutations cause mislocalization, linking subcellular targeting to loss of tumor-suppressor function.

    Evidence Site-directed mutagenesis of NLS variants, GFP/EGFP constructs, confocal microscopy and nuclear/cytoplasmic fractionation

    PMID:16116486 PMID:16964291

    Open questions at the time
    • Import receptor mediating NLS recognition not identified
    • Monopartite versus bipartite NLS boundaries differ between studies
  4. 2008 High

    Knockout mouse models and direct promoter occupancy studies established CDC73 as an essential gene that directly represses c-myc and regulates growth/survival genes, defining its anti-proliferative mechanism.

    Evidence Conventional and conditional knockout mice, MEF transcriptomics, ChIP, RT-PCR, plus RNAi/ChIP/epistasis at the c-myc locus

    PMID:18212049 PMID:18987311

    Open questions at the time
    • Mechanism distinguishing repressed versus activated targets not defined
    • Embryonic lethality limits tissue-specific dissection
  5. 2009 High

    Linking CDC73 to SUV39H1-mediated H3K9 methylation and to CPSF/CstF-dependent 3' processing extended its mechanism from elongation to chromatin repression and mRNA maturation.

    Evidence Co-IP with deletion mapping, ChIP, RNAi, and in vitro mRNA processing assays with immunodepletion

    PMID:19136632 PMID:19906718

    Open questions at the time
    • Whether 3' processing and transcriptional roles are mechanistically separable unresolved
    • Genome-wide scope of CPSF/CstF coupling not mapped
  6. 2009 Medium

    Demonstration of direct Gli binding generalized parafibromin's co-activator role beyond Wnt to the Hedgehog pathway.

    Evidence Co-IP, RNAi in Drosophila and mammalian cells, Hedgehog reporter assays

    PMID:19368795

    Open questions at the time
    • Competition between Gli and beta-catenin binding not yet examined at this stage
    • Structural basis of Gli interaction undefined
  7. 2011 High

    Discovery of the SHP2 tyrosine dephosphorylation switch resolved the repressor/activator paradox, showing a single post-translational signal toggles parafibromin between tumor-suppressive and oncogenic outputs.

    Evidence In vitro phosphatase assay, Co-IP, reporter assays, phosphorylation-state mapping

    PMID:21726809

    Open questions at the time
    • Upstream signals controlling SHP2 activity toward parafibromin unidentified
    • Specific phosphotyrosine residues and counteracting kinase not yet defined here
  8. 2011 High

    Identification of RNF20/RNF40 binding connected CDC73 to H2B-K120 monoubiquitination, adding a second histone-modification arm to its chromatin function.

    Evidence Yeast two-hybrid, Co-IP, RNAi, H2B-K120ub Western blot, tumor immunohistochemistry

    PMID:22021426

    Open questions at the time
    • Functional consequence of H2B ubiquitination loss for specific target genes not delineated
  9. 2012 High

    Crystallization of the yeast Cdc73 C-terminal Ras-like domain provided structural rationale for its role in elongation and chromatin association and for the clustering of clinical mutations in this region.

    Evidence Crystal structure, deletion analysis, yeast genetics, ChIP

    PMID:22318720

    Open questions at the time
    • Whether the Ras-like surface binds a GTPase or other partner unknown
    • No nucleotide-binding activity demonstrated
  10. 2014 Medium

    Defining a cytoplasmic role in destabilizing p53 mRNA revealed a transcription-independent oncogenic function for CDC73 acting through RNA decay machinery.

    Evidence RNA-IP, Co-IP with eEF1Bgamma and hSki8, mRNA stability assays, RNAi, cancer mutant analysis

    PMID:25388829

    Open questions at the time
    • Single lab; reciprocal validation of eEF1Bgamma/hSki8 RNA-decay complex limited
    • Signal partitioning CDC73 between nucleus and cytoplasm unclear
  11. 2015 Medium

    A genome-wide screen placed CDC73 in homologous recombination DNA repair, linking it to SCF/Cullin and INO80/NuA4 chromatin remodeling at damage sites independently of elongation.

    Evidence Genome-wide siRNA screen with RAD51 foci, recombination repair and RPA foci assays, Co-IP

    PMID:27462432

    Open questions at the time
    • Direct enzymatic role at break sites not established
    • Interaction with INO80/NuA4 not reciprocally mapped
  12. 2016 High

    Showing competitive, mutually exclusive binding to beta-catenin, Gli1, and NICD, all tuned by SHP2/PTK6, established parafibromin as an integrating hub coordinating Wnt, Hedgehog, and Notch output, with in vivo intestinal phenotypes.

    Evidence Competitive binding and reporter assays, Co-IP, conditional knockout mice with intestinal phenotyping

    PMID:27650679

    Open questions at the time
    • Quantitative rules governing pathway selection not defined
    • Tissue-specific kinase/phosphatase balance not mapped
  13. 2017 High

    High-resolution structure of the CDC73 N-terminal domain explained how HPT-JT missense mutations destabilize the protein, providing a structural basis for loss of function.

    Evidence Limited proteolysis, X-ray crystallography at 1.02 A, biochemical stability assays, mutant analysis

    PMID:29142233

    Open questions at the time
    • Binding partner engaged by the NTD hydrophobic groove not identified
  14. 2018 Medium

    Extending the phospho-switch to YAP/TAZ and identifying the Spt6 elongation-factor contact (in yeast) further refined how phosphorylation state and elongation machinery shape parafibromin co-activator selectivity.

    Evidence Co-IP and reporter assays for YAP/TAZ; yeast site-specific cross-linking, in vitro binding, rapid depletion and genome-wide ChIP for Spt6

    PMID:30227954 PMID:36928138

    Open questions at the time
    • YAP/TAZ findings single lab without in vivo confirmation
    • Conservation of Spt6 contact in human PAF1 complex not tested
  15. 2022 Medium

    Identification of UBR5-mediated, phospho-dependent polyubiquitination of CDC73 added a degradation layer controlling parafibromin levels and downstream beta-catenin/E-cadherin and immune phenotypes in breast cancer.

    Evidence Co-IP, ubiquitination assays, mutagenesis of acceptor lysines and Ser465, in vitro degradation assay

    PMID:35551175

    Open questions at the time
    • Single lab; physiological signals triggering UBR5 targeting unknown
    • Interplay with SHP2/PTK6 phospho-switch not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the competing nuclear (PAF1 elongation, repression, co-activation, DNA repair) and cytoplasmic (mRNA destabilization, actin bundling) activities of parafibromin are coordinately regulated in a cell-type-specific manner, and which functions are most relevant to tumor suppression, remains unresolved.
  • No unified model integrating phospho-switch, ubiquitination, and localization control
  • Functional ranking of nuclear versus cytoplasmic roles in carcinogenesis undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 3 GO:0003723 RNA binding 2 GO:0042393 histone binding 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953854 Metabolism of RNA 3 R-HSA-4839726 Chromatin organization 2 R-HSA-1643685 Disease 1 R-HSA-73894 DNA Repair 1
Partners
CTNNB1CTR9LEO1PAF1PTK6PTPN11RNF20SUV39H1
Complex memberships
CPSF/CstF 3' processing complexPAF1 complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Parafibromin (CDC73) is a component of a human PAF1 complex that includes homologs of Leo1, Paf1, and Ctr9, and associates with non-phosphorylated and Ser2/Ser5-phosphorylated forms of the RNA polymerase II large subunit. Immunofluorescence confirmed nuclear localization. Cotransfection data suggested parafibromin can interact with a histone methyltransferase complex that methylates histone H3 on lysine 4. Some tumor-derived mutant forms of parafibromin lack association with hPaf1 complex members and the histone methyltransferase complex. Protein purification, 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 Ser5- and Ser2-phosphorylated forms of RNA polymerase II large subunit. 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, cell cycle analysis Molecular and cellular biology High 15923622
2006 Drosophila Hyrax and its human ortholog parafibromin, components of the PAF1 complex, 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, establishing a molecular mechanism in which the nuclear Wnt signaling complex directly engages the PAF1 complex to control transcriptional initiation and elongation by RNA Pol II. Genetic epistasis in Drosophila, direct binding assay (pulldown), transcriptional reporter assays, RNAi Cell High 16630820
2005 Parafibromin overexpression (wild-type but not Leu64Pro missense mutant) inhibits cell proliferation and blocks expression of cyclin D1. Subcellular fractionation and confocal microscopy demonstrated parafibromin expression in both cytoplasmic and nuclear compartments of normal parathyroid gland. Transient overexpression, proliferation assay, cyclin D1 expression analysis, subcellular fractionation, laser confocal microscopy Oncogene Medium 15580289
2006 Parafibromin has a functional monopartite nuclear localization signal (NLS) at residues 136-139 (KKXR motif), identified by systematic deletion/mutation of predicted NLS sequences; mutation of this NLS abolishes nuclear localization. Over 60% of all parafibromin mutations lead to loss of this NLS. Site-directed mutagenesis, GFP-tagged constructs, confocal fluorescence microscopy, Western blot of nuclear/cytoplasmic fractions in COS-7 and HEK293 cells Oncogene High 16964291
2005 Parafibromin contains a functional bipartite nuclear localization signal (NLS) 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. EGFP-tagged wild-type and mutant parafibromin expression, confocal microscopy Oncogene Medium 16116486
2007 Nuclear localization of parafibromin enhances its proapoptotic function. NLS-mutant parafibromin is significantly impaired in association with endogenous Paf1 and Leo1. Overexpression of wild-type but not NLS-mutant parafibromin induces apoptosis. RNAi knockdown of endogenous parafibromin inhibits basal apoptosis and apoptosis resulting from DNA damage (camptothecin treatment). Site-directed mutagenesis, NLS mutation, co-immunoprecipitation, RNAi, apoptosis assays Molecular cancer research Medium 17314275
2008 Parafibromin tumor suppressor protein inhibits cell proliferation and represses the c-myc proto-oncogene. RNAi knockdown of parafibromin or Paf1 stimulates cell proliferation and increases c-myc protein levels via both c-myc protein stabilization and activation of the c-myc promoter. Chromatin immunoprecipitation demonstrates occupancy of the c-myc promoter by parafibromin and other PAF1 complex subunits. Knockdown of c-myc blocks the proliferative effect of parafibromin RNAi. RNAi, cell proliferation assay, Western blot, chromatin immunoprecipitation (ChIP), epistasis by double knockdown Proceedings of the National Academy of Sciences High 18987311
2009 Parafibromin interacts with the histone methyltransferase SUV39H1 through its central region (residues 128-227) and functions as a transcriptional repressor. Parafibromin associates with the promoter and coding regions of cyclin D1 and is required for recruitment of SUV39H1 and induction of H3 K9 methylation (but not H3 K4 methylation) at the cyclin D1 locus, leading to repression. Co-immunoprecipitation, deletion mapping, ChIP, RNAi Nucleic acids research High 19906718
2009 Cdc73/parafibromin physically associates with the cleavage and polyadenylation specificity factor (CPSF) and cleavage stimulation factor (CstF) complexes. Immunodepletion of Cdc73-CPSF-CstF complex abolishes 3' mRNA processing in vitro. CDC73 siRNA depletion results in decreased INTS6 mRNA and decreased association of CPSF and CstF subunits with the INTS6 locus. Co-immunoprecipitation, in vitro mRNA processing assay with immunodepletion, microarray analysis, ChIP Proceedings of the National Academy of Sciences High 19136632
2011 SHP2 tyrosine phosphatase dephosphorylates parafibromin/Cdc73 on tyrosine residues. Upon dephosphorylation by SHP2, parafibromin acquires the ability to stably bind beta-catenin. The parafibromin/beta-catenin interaction overrides parafibromin/SUV39H1-mediated transrepression and induces expression of Wnt target genes including cyclin D1 and c-myc. Thus SHP2 governs the switch between parafibromin's tumor-suppressive and oncogenic functions. In vitro phosphatase assay, co-immunoprecipitation, reporter gene assays, phosphorylation-state mapping Molecular cell High 21726809
2011 CDC73 interacts with ring finger proteins RNF20 and RNF40 (which form the E3 ubiquitin ligase for H2B-K120 monoubiquitination), identified by yeast two-hybrid. RNF20 and RNF40 bind to discrete but closely located residues on CDC73. Loss of nuclear CDC73 (by siRNA or tumor mutations) significantly reduces monoubiquitinated H2B-K120. H3-K4me3 was not changed by CDC73 loss, indicating these modifications are not always tightly linked. Yeast two-hybrid, co-immunoprecipitation, RNAi knockdown, analysis of H2B-K120 monoubiquitination by Western blot, immunohistochemistry in CDC73-mutant tumors Human molecular genetics High 22021426
2008 Parafibromin (in the PAF complex) directly regulates genes involved in cell growth and survival including H19, Igf1, Igf2, Igfbp4, Hmga1, Hmga2, and Hmgcs2, as demonstrated by cDNA microarray, RT-PCR, and ChIP in parafibromin-null mouse embryonic fibroblasts. Hrpt2-/- mice are embryonic lethal by E6.5 and conditional deletion in adults causes cachexia and death within 20 days. Hrpt2-/- MEFs undergo apoptosis. Conventional and conditional knockout mice, MEF culture, cDNA microarray, ChIP, RT-PCR, apoptosis assays Molecular and cellular biology High 18212049
2010 Parafibromin regulates 3' processing of replication-dependent histone mRNA. Downregulation of parafibromin by RNAi or tumor-associated mutations leads to uncleaved histone mRNA with polyadenylated tails, revealing a posttranscriptional role for parafibromin. RNAi knockdown, in vivo mutation analysis, histone mRNA 3' processing assay Molecular carcinogenesis Medium 19908240
2008 Parafibromin interacts with muscle alpha-actinins (actinin-2 and actinin-3) but not non-muscle alpha-actinins (actinin-1 and actinin-4) 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 cytoplasmic compartment, whereas in undifferentiated myoblasts it is predominantly nuclear. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, actin sedimentation assay, confocal microscopy Molecular cancer Medium 18687124
2006 Parafibromin inhibits cancer cell colony formation and proliferation and causes G1 phase cell cycle arrest when overexpressed. HPT-JT syndrome-derived mutations in HRPT2 behave in a dominant-negative manner by abolishing the ability of parafibromin to suppress cell proliferation. Colony formation assay, cell proliferation assay, cell cycle analysis (flow cytometry), dominant-negative overexpression of mutant constructs Biochemical and biophysical research communications Medium 16989776
2009 Parafibromin/Hyrax directly binds Region 1 (the Su(fu) interaction domain) in the N-terminus of all three Gli proteins and Ci in Drosophila, forming complexes with Gli1, Gli2, and Gli3. RNAi knockdown of Hyrax impairs Hedgehog pathway activity in Drosophila cells. RNAi knockdown of Parafibromin in mammalian cells diminishes transcriptional activity of Gli1 and Gli2. Co-immunoprecipitation, RNAi in Drosophila cells and mammalian cells, Hh reporter assay, genetic overexpression in vivo Mechanisms of development Medium 19368795
2012 The Cdc73 subunit of the yeast Paf1 complex contains a C-terminal Ras-like domain (C-domain). The crystal structure of this domain reveals similarity to the Ras family of small GTPases with a large flat conserved surface. Deletion of the C-domain causes elongation defects and reduced chromatin association for multiple Paf1 complex subunits without loss of complex integrity. Simultaneous mutation of the C-domain and Rtf1 causes loss of H3K36 trimethylation. Crystal structure determination, deletion analysis, yeast genetics, chromatin immunoprecipitation Journal of biological chemistry High 22318720
2014 Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis. hCdc73 associates with mature p53 mRNA in the cytoplasm and facilitates its degradation by physically interacting with eEF1Bγ and hSki8; these interactions are required for binding and destabilizing p53 mRNA. A cancer-derived hCdc73(K34Q) mutant showed enhanced association with p53 mRNA, resulting in reduced p53 expression and enhanced cell proliferation. RNA immunoprecipitation, co-immunoprecipitation, mRNA stability assay, RNAi, overexpression of mutant constructs Nature communications Medium 25388829
2015 CDC73/Parafibromin is required for homologous recombination repair of ionizing radiation-induced DNA damage. CDC73 interacts with components of the SCF/Cullin and INO80/NuA4 chromatin-remodeling complexes to promote histone ubiquitination at sites of DNA damage, facilitating local chromatin decondensation for DNA repair. This function is related to but independent of its role in transcriptional elongation. Genome-wide siRNA screen with RAD51 foci readout, validation by independent siRNAs, recombination repair activity assay, RPA foci formation assay, co-immunoprecipitation Cell discovery Medium 27462432
2016 Dephosphorylated parafibromin competitively interacts with both beta-catenin and Gli1, potentiating Wnt and Hedgehog target gene transactivation in a mutually exclusive manner. Parafibromin also binds the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes. Tyrosine dephosphorylation by SHP2 phosphatase potentiates, while tyrosine phosphorylation by PTK6 kinase attenuates, the transcriptional platform function of parafibromin. Acute loss of parafibromin in mice disorganizes the normal epithelial architecture of the intestine. Co-immunoprecipitation, reporter assays, competitive binding assay, conditional knockout mice, intestinal phenotype analysis Nature communications High 27650679
2018 YAP and TAZ transcriptional co-activator functions are inversely regulated by the tyrosine phosphorylation status of parafibromin. TAZ and Wnt effector beta-catenin interact cooperatively with tyrosine-dephosphorylated parafibromin, synergistically stimulating co-activator functions. YAP is selectively activated through binding with tyrosine-phosphorylated parafibromin, which does not interact with beta-catenin. Thus YAP and TAZ exert redundant and non-redundant functions through mutually exclusive interaction with parafibromin regulated by kinase/phosphatase balance. Co-immunoprecipitation, reporter assays, phosphorylation-state analysis, mutant overexpression iScience Medium 30227954
2015 Parafibromin is a component of IFN-γ-triggered signaling pathways. Parafibromin interacts with JAK1 and JAK2, promotes JAK1-JAK2 and JAK1/2-STAT1 interactions, and promotes tyrosine phosphorylation of STAT1 at Tyr701 after IFN-γ stimulation. Overexpression of parafibromin enhanced IFN-γ-triggered STAT1 phosphorylation and downstream gene expression; knockdown had opposite effects. Co-immunoprecipitation, overexpression, RNAi knockdown, STAT1 phosphorylation assay, antiviral response assay Journal of immunology Medium 26232434
2022 UBR5 E3 ubiquitin ligase targets CDC73 for proteasomal degradation by polyubiquitination at Lys243, Lys247, and Lys257. This ubiquitination depends on the non-phosphorylated state of CDC73 at Ser465. CDC73 degradation by UBR5 regulates beta-catenin and E-cadherin expression, tumor cell apoptosis, and CD8+ T cell infiltration in triple-negative breast cancer. Co-immunoprecipitation, ubiquitination assay, mutagenesis of ubiquitin acceptor sites and phosphorylation site, in vitro degradation assay Cell death and disease Medium 35551175
2017 Crystal structure of the human CDC73 N-terminal domain (residues 1-111) was determined at 1.02 Å resolution, revealing a novel protein fold with an extended hydrophobic groove. Most pathogenic HPT-JT-associated missense mutations are located in the region encoding CDC73-NTD and disrupt the folding of the hydrophobic core, while others (e.g., K34Q) reduce thermostability. Limited proteolysis, X-ray crystallography, biochemical stability assays, mutant analysis Scientific reports High 29142233
2010 The L95P missense mutant parafibromin is markedly deficient in nucleolar localization (disrupting a putative nucleolar localization signal immediately upstream of L95P), while retaining ability to assemble with endogenous PAF1 complex components by co-immunoprecipitation. Transfection of L95P parafibromin enhances cell cycle progression and cell survival, acting as a dominant-negative inhibitor of endogenous parafibromin. Subcellular localization by confocal microscopy, co-immunoprecipitation, cell cycle and cell survival assays with dominant-negative mutant Endocrine-related cancer Medium 20304979
2015 LEOPARD syndrome-associated SHP2 mutants (Y279C, T468M, Q506P, Q510E) exhibit substantially reduced phosphatase activity toward tyrosine-phosphorylated parafibromin compared to wild-type SHP2, as demonstrated in a direct in vitro phosphatase assay using parafibromin as substrate. Each LS-associated mutant displayed a differential degree of decrease in phosphatase activity. In vitro phosphatase assay with tyrosine-phosphorylated parafibromin as substrate Biochemical and biophysical research communications Medium 26742426
2018 In S. cerevisiae, Cdc73 directly interacts with two components of the RNA Pol II elongation complex: the elongation factor Spt6 and the largest subunit of Pol II, both interactions requiring the tandem SH2 domain of Spt6. Rapid depletion of Spt6 dissociates Paf1 from chromatin and alters Paf1C-dependent histone modifications genome-wide. Cdc73 and Spt6 can interact in vitro. Site-specific protein cross-linking in yeast, in vitro binding assay, rapid depletion/ChIP, genome-wide histone modification analysis Nucleic acids research High 36928138
2018 In S. cerevisiae, Cdc73 suppresses genome instability by mediating telomere homeostasis. Loss of Cdc73 increases gross chromosomal rearrangement (GCR) rates. A central 105 amino acid region of Cdc73 is necessary and sufficient for suppressing GCR defects; this region mediates binding of Cdc73 to the Paf1 complex through Ctr9 and is required for nuclear localization. Synergistic increases in GCRs occur when cdc73Δ is combined with tel1Δ or yku80Δ, and telomere length defects are enhanced. GCR rate assay, genome sequencing of GCRs, deletion mapping of Cdc73, telomere length analysis, genetic epistasis PLoS genetics Medium 29320491
2012 MiR-155 negatively regulates CDC73 expression at the post-transcriptional level by targeting CDC73 mRNA. Ectopic expression of miR-155 in HEK293 cells reduced CDC73 levels, enhanced cell viability, and decreased apoptosis. Delivery of miR-155 antagomir to KB cells restored CDC73 levels, decreased cell viability, and increased apoptosis. Co-transfection of miR-155 with CDC73 (without 3'-UTR) abrogated the pro-oncogenic effect of miR-155. MiR-155 overexpression and antagomir delivery, Western blot for CDC73, cell viability and apoptosis assays, 3'-UTR-dependent expression analysis, xenograft tumor model Journal of biological chemistry Medium 23166327
2013 WT1 (Wilms tumor 1 protein) transcriptionally represses CDC73 by binding to the CDC73 promoter. ChIP and EMSA demonstrated direct WT1 binding to the CDC73 promoter. Overexpression of WT1 decreased CDC73 levels and promoted proliferation of OSCC cells. Exogenous CDC73 attenuated the pro-tumorigenic activity of WT1. ChIP, EMSA, overexpression, knockdown, proliferation/apoptosis assays, 5-azacytidine treatment Journal of biological chemistry Medium 24257751
2020 Disruption of the C-terminal domain (CTD) of parafibromin by germline CDC73 mutations is directly associated with predisposition to parathyroid carcinoma. High-impact mutations predicted to cause conformational disruption or loss of expression of parafibromin confer a 6.6-fold higher risk of parathyroid carcinoma compared to low-impact mutations. Structural analysis revealed a conserved surface structure in the CTD that is universally disrupted by carcinoma-associated mutations. Cohort analysis of mutation carriers with Kaplan-Meier analysis, structural modeling of CTD mutations Endocrine-related cancer Low 32590342

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 511 12434154
2003 Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. The New England journal of medicine 399 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 230 15632063
1995 Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. American journal of human genetics 188 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 155 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 101 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 94 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
2005 HRPT2 mutational analysis of typical sporadic parathyroid adenomas. The Journal of clinical endocrinology and metabolism 83 15956079
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 74 29324469
2017 CDC73-Related Disorders: Clinical Manifestations and Case Detection in Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism 74 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 72 22021426
2006 Loss of parafibromin expression in a subset of parathyroid adenomas. Endocrine-related cancer 70 16728578
2007 Identification of MEN1 and HRPT2 somatic mutations in paraffin-embedded (sporadic) parathyroid carcinomas. Clinical endocrinology 69 17555500
2013 CDC73 mutational status and loss of parafibromin in the outcome of parathyroid cancer. Endocrine connections 68 24145611
2006 Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance. The Journal of clinical endocrinology and metabolism 68 16720667
2009 The tumor suppressor, parafibromin, mediates histone H3 K9 methylation for cyclin D1 repression. Nucleic acids research 66 19906718
2006 Parafibromin inhibits cancer cell growth and causes G1 phase arrest. Biochemical and biophysical research communications 64 16989776
2006 Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal. Oncogene 63 16964291
2012 CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort. Cellular oncology (Dordrecht, Netherlands) 60 22987117
2009 Parafibromin--functional insights. Journal of internal medicine 60 19522828
2006 Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 58 16995822
2004 Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene. The Journal of clinical endocrinology and metabolism 53 15070940
2010 Parafibromin and APC as screening markers for malignant potential in atypical parathyroid adenomas. Endocrine pathology 52 20473645
2012 Cdc73 subunit of Paf1 complex contains C-terminal Ras-like domain that promotes association of Paf1 complex with chromatin. The Journal of biological chemistry 51 22318720
2007 Nuclear localization of the parafibromin tumor suppressor protein implicated in the hyperparathyroidism-jaw tumor syndrome enhances its proapoptotic function. Molecular cancer research : MCR 49 17314275
2008 Clinical, genetic, and histopathologic investigation of CDC73-related familial hyperparathyroidism. Endocrine-related cancer 48 18755853
2005 Identification of a functional bipartite nuclear localization signal in the tumor suppressor parafibromin. Oncogene 48 16116486
2008 Familial hyperparathyroidism: surgical outcome after 30 years of follow-up in three families with germline HRPT2 mutations. Surgery 47 18436011
2005 Dental findings in a family with hyperparathyroidism-jaw tumor syndrome and a novel HRPT2 gene mutation. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 46 16448924
2016 Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways. Nature communications 44 27650679
2012 Novel HRPT2/CDC73 gene mutations and loss of expression of parafibromin in Chinese patients with clinically sporadic parathyroid carcinomas. PloS one 42 23029104
2011 Parafibromin immunohistochemical staining to differentiate parathyroid carcinoma from parathyroid adenoma. Head & neck 41 21717519
2009 The role of Parafibromin/Hyrax as a nuclear Gli/Ci-interacting protein in Hedgehog target gene control. Mechanisms of development 41 19368795
2004 A Novel IVS2-1G>A mutation causes aberrant splicing of the HRPT2 gene in a family with hyperparathyroidism-jaw tumor syndrome. The Journal of clinical endocrinology and metabolism 40 15613436
2018 Transcriptional Co-activator Functions of YAP and TAZ Are Inversely Regulated by Tyrosine Phosphorylation Status of Parafibromin. iScience 39 30227954
2014 CDC73 intragenic deletion in familial primary hyperparathyroidism associated with parathyroid carcinoma. The Journal of clinical endocrinology and metabolism 39 24823466
2010 PLANT HOMOLOGOUS TO PARAFIBROMIN is a component of the PAF1 complex and assists in regulating expression of genes within H3K27ME3-enriched chromatin. Plant physiology 39 20363855
2006 Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene. Oncogene 39 17130827
2020 Genotype of CDC73 germline mutation determines risk of parathyroid cancer. Endocrine-related cancer 36 32590342
2019 Parafibromin immunostainings of parathyroid tumors in clinical routine: a near-decade experience from a tertiary center. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 36 30923346
2011 Detection of the first gross CDC73 germline deletion in an HPT-JT syndrome family. Genes, chromosomes & cancer 35 21837707
2005 Utilisation of a cryptic non-canonical donor splice site of the gene encoding PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism. Journal of medical genetics 35 16061557
2015 A genome-wide IR-induced RAD51 foci RNAi screen identifies CDC73 involved in chromatin remodeling for DNA repair. Cell discovery 32 27462432
2012 Identification of the first germline HRPT2 whole-gene deletion in a patient with primary hyperparathyroidism. Clinical endocrinology 32 21790700
2011 Absence of nucleolar parafibromin immunoreactivity in subsets of parathyroid malignant tumours. Virchows Archiv : an international journal of pathology 32 21221636
2010 CDC73/HRPT2 CpG island hypermethylation and mutation of 5'-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors. Endocrine-related cancer 32 20026646
2020 Circ_0000140 restrains the proliferation, metastasis and glycolysis metabolism of oral squamous cell carcinoma through upregulating CDC73 via sponging miR-182-5p. Cancer cell international 30 32863766
2017 Parafibromin, APC, and MIB-1 Are Useful Markers for Distinguishing Parathyroid Carcinomas From Adenomas. Applied immunohistochemistry & molecular morphology : AIMM 30 27490759
2012 Expression of Ki-67, galectin-3, fragile histidine triad, and parafibromin in malignant and benign parathyroid tumors. Chinese medical journal 30 22932087
2011 CDC73-related hereditary hyperparathyroidism: five new mutations and the clinical spectrum. European journal of endocrinology 30 21652691
2010 The tumor suppressor parafibromin is required for posttranscriptional processing of histone mRNA. Molecular carcinogenesis 29 19908240
2007 Aberrant methylation of the HRPT2 gene in parathyroid carcinoma. The Annals of otology, rhinology, and laryngology 29 18217513
2008 The parafibromin tumor suppressor protein interacts with actin-binding proteins actinin-2 and actinin-3. Molecular cancer 28 18687124
2007 Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation. Endocrine-related cancer 28 17639062
2014 Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis. Nature communications 27 25388829
2013 Transcriptional repression of tumor suppressor CDC73, encoding an RNA polymerase II interactor, by Wilms tumor 1 protein (WT1) promotes cell proliferation: implication for cancer therapeutics. The Journal of biological chemistry 27 24257751
2010 Defective nucleolar localization and dominant interfering properties of a parafibromin L95P missense mutant causing the hyperparathyroidism-jaw tumor syndrome. Endocrine-related cancer 27 20304979
2007 Parafibromin tumor suppressor enhances cell growth in the cells expressing SV40 large T antigen. Oncogene 27 17404568
2014 Characterization of a new CDC73 missense mutation that impairs Parafibromin expression and nucleolar localization. PloS one 26 24842573
2011 Familial hyperparathyroidism due to a germline mutation of the CDC73 gene: implications for management and age-appropriate testing of relatives at risk. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 25 21324824
2006 Immunohistochemical assessment of parafibromin in mouse and human tissues. Journal of anatomy 25 17118068
2023 Spt6 directly interacts with Cdc73 and is required for Paf1 complex occupancy at active genes in Saccharomyces cerevisiae. Nucleic acids research 24 36928138
2009 Mutation analysis of MEN1, HRPT2, CASR, CDKN1B, and AIP genes in primary hyperparathyroidism patients with features of genetic predisposition. Journal of endocrinological investigation 23 19474519
2005 HRPT2, a tumor suppressor gene for hyperparathyroidism-jaw tumor syndrome. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 23 16001331
2014 Familial isolated primary hyperparathyroidism/hyperparathyroidism-jaw tumour syndrome caused by germline gross deletion or point mutations of CDC73 gene in Chinese. Clinical endocrinology 22 24716902
2010 Parafibromin as a diagnostic instrument for parathyroid carcinoma-lone ranger or part of the posse? International journal of endocrinology 21 21197463
2022 UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer. Cell death & disease 20 35551175
2018 CDC73 Germline Mutation in a Family With Mixed Epithelial and Stromal Tumors. Urology 20 30452964
2016 CDC73 gene mutations in sporadic ossifying fibroma of the jaws. Diagnostic pathology 20 27658992
2015 Parafibromin Is a Component of IFN-γ-Triggered Signaling Pathways That Facilitates JAK1/2-Mediated Tyrosine Phosphorylation of STAT1. Journal of immunology (Baltimore, Md. : 1950) 20 26232434
2017 Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Scientific reports 19 29142233
2016 A germline mutation of HRPT2/CDC73 (70 G>T) in an adolescent female with parathyroid carcinoma: first case report and a review of the literature. Journal of pediatric endocrinology & metabolism : JPEM 19 27544721
2015 Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling. Biochemical and biophysical research communications 19 26742426
2013 Assessing the contribution of HRPT2 to the pathogenesis of jaw fibrous dysplasia, ossifying fibroma, and osteosarcoma. Oral surgery, oral medicine, oral pathology and oral radiology 19 23453027
2012 Genome-wide and locus specific alterations in CDC73/HRPT2-mutated parathyroid tumors. PloS one 18 23029479
2011 Identification of de novo germline mutations in the HRPT2 gene in two apparently sporadic cases with challenging parathyroid tumor diagnoses. Endocrine pathology 17 21360064
2007 Parafibromin expression, single-gland involvement, and limited parathyroidectomy in familial isolated hyperparathyroidism. Surgery 17 18063086
2018 Cdc73 suppresses genome instability by mediating telomere homeostasis. PLoS genetics 16 29320491
2015 The Role of Parafibromin, Galectin-3, HBME-1, 
and Ki-67 in the Differential Diagnosis of Parathyroid Tumors. Oman medical journal 16 26675091
2011 Novel nonsense CDC73 mutations in Chinese patients with parathyroid tumors. Familial cancer 16 21732217
2008 Hyperparathyroidism 2 gene (HRPT2, CDC73) and parafibromin studies in two patients with primary hyperparathyroidism and uncertain pathological assessment. Journal of endocrinological investigation 16 19092296
2022 Diagnostic significance of parafibromin expression in parathyroid carcinoma. Human pathology 15 35654240

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