Affinage

DKC1

H/ACA ribonucleoprotein complex subunit DKC1 · UniProt O60832

Length
514 aa
Mass
57.7 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Dyskerin (DKC1) is the catalytic pseudouridine synthase subunit of H/ACA ribonucleoprotein complexes that modifies uridines in rRNA, snRNA, and mRNA and serves as an obligate component of telomerase (PMID:10523634, PMID:15240872, PMID:32554502). Within the H/ACA RNP, dyskerin (yeast Cbf5) catalyzes site-specific pseudouridylation through a conserved active-site aspartate (D95 in yeast, D125 in mouse), and active-site mutation abolishes rRNA pseudouridylation and impairs snoRNA association (PMID:10523634, PMID:23726835); structural studies show that Nop10 buttresses the catalytic cleft and that Nop10 and Gar1 both raise the catalytic rate, making them essential cofactors of the enzyme (PMID:16286935, PMID:16427014, PMID:22993689). Assembly of the catalytic core is chaperoned by SHQ1, which binds the dyskerin PUA domain and C-terminal extension to protect it from premature, non-specific RNA binding before H/ACA RNA loading (PMID:22117216, PMID:29178645). rRNA pseudouridylation stabilizes rRNA secondary structure and is required for normal rRNA processing, nucleolar fibrillarin accumulation, and faithful, IRES-competent ribosome activity; loss of dyskerin triggers p53-dependent checkpoint activation and apoptosis (PMID:19917719, PMID:25934701, PMID:23726835). In a guide-independent, cotranscriptional mode, dyskerin associates with RNA polymerase II and pseudouridylates thousands of mRNAs to suppress their translation (PMID:37506213). Independent of catalysis on rRNA, dyskerin is essential for telomerase: it binds directly to the H/ACA motif of hTR via N-terminal residues and protects hTR from PAPD5-dependent oligoadenylation and EXOSC10/DCP2/XRN1-mediated decay (PMID:19835419, PMID:26950371, PMID:30931479). Its nuclear/nucleolar localization, governed by a C-terminal localization signal and SUMOylation at K467, is required for both H/ACA RNP and telomerase function (PMID:10556300, PMID:33526451). Dyskerin is a direct transcriptional target of c-MYC and GATA1 and acts as an OCT4/SOX2 coactivator at pluripotency enhancers, and its activities further shape translation of tumor suppressors and ribosomal-protein mRNAs that modulate RAS/RAF/MEK/ERK signaling (PMID:17822678, PMID:25407680, PMID:31413099, PMID:34026451). Pathogenic DKC1 mutations cause dyskeratosis congenita, acting at the dyskerin–NOP10 and hTR-binding interfaces to reduce pseudouridylation and telomerase activity (PMID:32554502, PMID:19835419).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1994 High

    Established the protein's nucleolar identity by placing NAP57/dyskerin physically with Nopp140 in the dense fibrillar component and coiled bodies, the sites of rRNA modification.

    Evidence Reciprocal co-IP with immunofluorescence and immunogold EM in mammalian cells

    PMID:7798307

    Open questions at the time
    • Did not define an enzymatic activity
    • Functional consequence of the Nopp140 association unresolved
  2. 1999 High

    Identified dyskerin as the pseudouridine synthase of H/ACA snoRNPs and pinpointed the catalytic aspartate, defining its core enzymatic function.

    Evidence Active-site mutagenesis (D95A) with in vivo rRNA pseudouridylation and snoRNA association assays in yeast Cbf5p

    PMID:10523634

    Open questions at the time
    • Did not address telomerase role
    • Mechanism of guide RNA selection not resolved
  3. 1999 High

    Mapped the determinants of dyskerin's nuclear/nucleolar trafficking, establishing where the enzyme must concentrate to act.

    Evidence EGFP live-cell imaging and deletion mapping of NLS/C-terminal lysine clusters in mammalian cells

    PMID:10556300 PMID:10744426

    Open questions at the time
    • Did not link localization to catalytic or telomerase output
    • Regulation of trafficking unaddressed
  4. 2004 High

    Demonstrated in a mammalian system that disease mutations partition dyskerin's two functions, separating effects on rRNA pseudouridylation from telomerase RNA stability.

    Evidence Knock-in mutant (A353V, G402E) mouse ES cells with TRAP, pseudouridylation, and telomere length assays

    PMID:15240872

    Open questions at the time
    • Structural basis of mutation-specific effects not defined
    • Did not resolve which defect drives disease
  5. 2005 High

    Provided the structural logic for catalysis by showing Nop10 buttresses the Cbf5 active site and extends the RNA-binding cleft.

    Evidence 1.95-Å crystal structure of archaeal Cbf5-Nop10 with mutagenesis and cross-species assembly

    PMID:16286935

    Open questions at the time
    • Full RNP with guide and substrate not yet captured
    • Human dyskerin structure inferred from archaeal ortholog
  6. 2006 High

    Extended the structural model to the Cbf5-Nop10-Gar1 complex, explaining cofactor essentiality and locating the dyskeratosis congenita mutation cluster on the PUA domain.

    Evidence 2.1-Å crystal structure with full RNP modeling and DC mutation mapping

    PMID:16427014

    Open questions at the time
    • Telomerase-specific RNP architecture not addressed
    • Catalytic kinetics of cofactors not quantified here
  7. 2007 Medium

    Placed DKC1 expression under direct oncogenic control by identifying it as a c-MYC transcriptional target, linking it to proliferative programs.

    Evidence Conditional c-MYC transgene with ChIP and cycloheximide treatment

    PMID:17822678

    Open questions at the time
    • Single lab
    • Downstream functional consequence of MYC-driven DKC1 not tested here
  8. 2008 High

    Showed pathogenic Dkc1 mutations trigger a telomere-localized DNA damage response independent of telomere shortening, refining the mechanism of disease pathology.

    Evidence Mouse knock-in with X-inactivation genetic epistasis and DNA damage foci imaging

    PMID:18626023

    Open questions at the time
    • Molecular trigger of telomere-localized damage unresolved
    • Relationship to pseudouridylation defect not separated
  9. 2009 High

    Defined the ribosome-biogenesis arm in vivo, showing dyskerin loss blocks rRNA processing and activates p53-dependent checkpoints, and demonstrated direct, mutation-sensitive binding to hTR.

    Evidence Conditional liver knockout (rRNA Northern, fibrillarin IF, TUNEL) and single-molecule TCCD of dyskerin-hTR binding with subdomain deletions

    PMID:19835419 PMID:19917719

    Open questions at the time
    • hTR-binding determinants on dyskerin not fully mapped at residue level
    • Did not resolve how hTR escapes degradation
  10. 2010 High

    Established a translational-control function by showing dyskerin is required for IRES-mediated translation of tumor suppressors p27 and p53, linking pseudouridylation to ribosome activity.

    Evidence p27 IRES reporter mouse with 48S preinitiation assembly assay, human tumor mutation (S485G), and siRNA with polysome profiling/IRES reporters

    PMID:20501855 PMID:20587522

    Open questions at the time
    • Direct molecular basis of IRES selectivity unresolved
    • p53 effect shown by siRNA in single lab
  11. 2011 High

    Identified SHQ1 as the assembly chaperone that protects nascent dyskerin from non-specific RNA before H/ACA loading, defining the maturation pathway of the catalytic core.

    Evidence Crystal structure of Shq1-Cbf5-Nop10-Gar1 with yeast genetics and binding competition

    PMID:22117216

    Open questions at the time
    • Hand-off mechanism from SHQ1 to H/ACA RNA not kinetically resolved
    • Human SHQ1-dyskerin interface inferred
  12. 2011 High

    Resolved the hTR decay pathway dyskerin protects against, placing PAPD5/EXOSC10/DCP2/XRN1 downstream of failed dyskerin binding.

    Evidence RNAi of decay factors with TRAP rescue, hTR localization, and decay analysis (PARN deadenylation)

    PMID:26950371

    Open questions at the time
    • Precise recognition step distinguishing protected vs degraded hTR not defined
  13. 2012 High

    Connected dyskerin to rRNA quality control via SMUG1 and quantified how Nop10/Gar1 accelerate catalysis, deepening the enzymatic and partner picture.

    Evidence Co-IP/RIP/colocalization with SMUG1 plus in vitro pseudouridylation kinetics with purified archaeal Cbf5-Nop10-Gar1

    PMID:22993689 PMID:23246433

    Open questions at the time
    • Functional importance of SMUG1 partnership in disease unclear
    • Kinetics measured on archaeal components and tRNA substrate
  14. 2013 High

    Resolved the catalytic requirement for rRNA stability and dissected mutation-specific RNP assembly defects, while establishing SUMOylation as a stability determinant and dyskerin's mitotic localization.

    Evidence Catalytic-dead D125A knock-in MEFs (rRNA stability), pre-RNP assembly assays of DC mutants, SUMO modification assays, cell-cycle imaging with siRNA, and bicistronic VEGF IRES reporters

    PMID:20008900 PMID:23660516 PMID:23726835 PMID:23821664 PMID:24303026 PMID:25934701

    Open questions at the time
    • Mechanism of opposite IRES effects (VEGF up vs p27/p53 down) unresolved
    • Mitotic and SUMO findings from single labs
  15. 2014 High

    Revealed a transcriptional-coactivator function distinct from catalysis, showing the dyskerin RNP supports OCT4/SOX2 at pluripotency enhancers and reprogramming.

    Evidence Biochemical purification from in vitro transcription system, ChIP-seq, and iPSC reprogramming with siRNA depletion

    PMID:25407680

    Open questions at the time
    • How snoRNAs modulate the coactivator activity not mechanistically defined
    • Whether catalysis is required unresolved
  16. 2016 Medium

    Identified SMN and coilin as negative regulators of dyskerin-hTR association, adding a regulatory layer to telomerase RNP assembly.

    Evidence Co-IP and siRNA knockdown of SMN/coilin with telomerase component association assays

    PMID:27215323

    Open questions at the time
    • Single lab
    • Direct vs indirect regulation not distinguished
  17. 2019 High

    Pinpointed N-terminal dyskerin residues required for hTR binding and clarified that hTR precursor degradation occurs upstream of mature complex assembly, while linking DKC1 to GATA1-driven erythroid telomerase and tumor angiogenesis.

    Evidence Co-IP/rescue/TRAP with K39E/K43E mutants; GATA1 ChIP/reporter in erythroid cells; HIF-1α ChIP in colorectal cancer

    PMID:30931479 PMID:31413099 PMID:31857720

    Open questions at the time
    • Erythroid and cancer ChIP findings from single labs
    • Whether DKC1 directly binds HIF-1α promoter vs acts via cofactor unresolved
  18. 2020 High

    Demonstrated across patient pedigrees, structure, and a vertebrate model that DKC1/NOP10 interface mutations disrupt the catalytic site and reduce rRNA pseudouridylation, causing a telomere-independent cell-cycle defect.

    Evidence Structural mapping, dyskerin-NOP10 interaction assays, patient rRNA pseudouridine quantification, zebrafish dkc1 model

    PMID:32554502

    Open questions at the time
    • Tissue-specific consequences of ribosomal dysregulation not fully defined
  19. 2021 High

    Uncovered a catalysis-dependent mRNA-stabilizing function for ribosomal-protein transcripts that suppresses RAS/RAF/MEK/ERK signaling, and refined the SUMO-localization axis.

    Evidence RIP-seq, RNA decay, D125A catalytic-mutant rescue, proteomics, xenografts; plus SUMO3-fusion localization and GAR1 SIM mapping

    PMID:33526451 PMID:34026451

    Open questions at the time
    • Mechanism by which DKC1 selects/stabilizes specific ribosomal-protein mRNAs unresolved
    • Link between mRNA stabilization and pseudouridylation catalysis not directly shown
  20. 2023 High

    Established a guide-independent, cotranscriptional mRNA pseudouridylation activity that suppresses translation, and identified SENP3-mediated deSUMOylation as a regulator of dyskerin stability and snoRNP integrity.

    Evidence Pseudouridine-seq, RNA Pol II co-IP, SUnSET/polysome profiling, patient cells; plus SENP3 co-IP, SUMO mapping, CRISPR knock-in, xenografts

    PMID:37188742 PMID:37506213

    Open questions at the time
    • How dyskerin selects mRNA target sites without guide RNA unresolved
    • Physiological scope of translational suppression across cell types unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How dyskerin's multiple functions — H/ACA catalysis, telomerase RNA protection, guide-independent mRNA modification, and transcriptional coactivation — are coordinated and differentially deployed across cell types remains unresolved.
  • No unified model linking localization/SUMO state to functional partitioning
  • Target-site selection rules for guide-independent mRNA pseudouridylation unknown
  • Relative contribution of ribosomal vs telomeric defects to disease unsettled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 7 GO:0003723 RNA binding 5 GO:0045182 translation regulator activity 5 GO:0016853 isomerase activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005730 nucleolus 5 GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1640170 Cell Cycle 3
Partners
GAR1HTR/TERCNAF1NHP2NOP10NOPP140SHQ1SMUG1
Complex memberships
H/ACA snoRNPtelomerase holoenzyme

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 NAP57 (DKC1) is associated with nucleolar protein Nopp140 in an apparently stoichiometric complex, as shown by coimmunoprecipitation. Immunofluorescence and immunogold EM show colocalization with Nopp140 to the dense fibrillar component of the nucleolus, coiled bodies, and nucleoplasm. Coimmunoprecipitation, immunofluorescence, immunogold electron microscopy The Journal of cell biology High 7798307
1999 Yeast Cbf5p (ortholog of DKC1/dyskerin) is the pseudouridine synthase component of H/ACA snoRNPs. Alanine substitution of the conserved aspartate in the XLD motif (D95A) abolishes in vivo pseudouridylation of rRNA. Catalytic domain mutations also impair association of Cbf5p with selected H/ACA snoRNAs. In vitro mutagenesis, in vivo pseudouridylation assay, growth phenotype analysis, snoRNA co-association assays Molecular and cellular biology High 10523634
1999 Dyskerin (DKC1) localizes to the nucleolus. EGFP-tagged full-length dyskerin initially accumulates in the nucleoplasm and subsequently concentrates in nucleoli and coiled bodies. The KRKR sequence is primarily responsible for nuclear import, while C-terminal lysine-rich clusters influence the rate of nucleoplasmic and nucleolar accumulation. Dyskerin mislocalization caused by DC mutations is unlikely to cause pathogenesis. EGFP fusion live-cell imaging, deletion/mutation analysis of NLS constructs, time-course expression in mammalian cell lines Human molecular genetics High 10556300
1999 Dyskerin nuclear entry requires a carboxyl-terminal domain (amino acids 467–475, KKEKKKSKK), which is both necessary and sufficient for nuclear localization. Dyskerin does not interact with FANCA (Fanconi anemia group A protein) in coimmunoprecipitation. Epitope-tagged transfection, immunofluorescence, deletion analysis, co-IP (negative result for FANCA interaction) Blood cells, molecules & diseases Medium 10744426
2004 Mouse dyskerin point mutations (A353V and G402E) cause defects in H/ACA snoRNA accumulation and site-specific pseudouridylation of rRNA. A353V, but not G402E, severely destabilizes telomerase RNA (TERC) and reduces telomerase activity with progressive telomere shortening in vitro. Both mutations impair overall pseudouridylation. Murine embryonic stem cell knock-in, TRAP telomerase assay, real-time PCR for snoRNAs and TERC, pseudouridylation assays, telomere length measurement Proceedings of the National Academy of Sciences of the United States of America High 15240872
2005 Crystal structure of archaeal Cbf5-Nop10 complex at 1.95-Å resolution reveals that Nop10 buttresses the active site of Cbf5 and reveals two basic troughs extending the active site cleft. Mutagenesis implicates an adjacent basic patch in RNA binding. Archaeal Cbf5 can assemble with yeast Nop10 and with human telomerase RNA, indicating phylogenetic conservation of this architecture. X-ray crystallography, mutagenesis, cross-species assembly assays Nature structural & molecular biology High 16286935
2006 Crystal structure of archaeal Cbf5-Nop10-Gar1 complex at 2.1 Å reveals unique structural features of Cbf5 among pseudouridine synthases consistent with RNA-guided catalysis. The structure reveals how Nop10 and Gar1 are essential for pseudouridylation and identifies a dyskeratosis congenita mutation cluster site in the modeled dyskerin PUA domain. X-ray crystallography, structural modeling of full RNP complex with guide and substrate RNAs, mapping of DC mutations Molecular cell High 16427014
2007 DKC1 is a direct transcriptional target of c-MYC. c-MYC activates DKC1 expression acutely, binds to two conserved regions in the DKC1 promoter and intron 1 as shown by chromatin immunoprecipitation, and this activation occurs in the absence of de novo protein synthesis. Conditionally active c-MYC transgene system, chromatin immunoprecipitation (ChIP), RT-PCR, cycloheximide treatment Biochemical and biophysical research communications Medium 17822678
2008 Pathogenic Dkc1 mutations in mice cause a growth disadvantage and enhanced DNA damage response (ATM/p53 pathway) with DNA damage foci colocalizing with telomeres, independent of telomere length shortening. The growth disadvantage depends on telomerase (shown by genetic experiments using X-inactivation disparity in female heterozygotes). Mouse knock-in model, X-inactivation pattern analysis (genetic epistasis), DNA damage foci immunofluorescence (co-localization with telomeres), etoposide treatment assay Proceedings of the National Academy of Sciences of the United States of America High 18626023
2009 Dyskerin ablation in mouse liver inhibits rRNA processing (accumulation of large precursors), prevents fibrillarin accumulation in nucleoli, induces low-level apoptosis and p53-dependent cell cycle checkpoint activation. Hepatocytes without dyskerin fail to proliferate in response to carbon tetrachloride-induced regeneration stimulus. Cre/loxP conditional knockout in mouse liver, Northern blot for rRNA precursors, immunofluorescence for fibrillarin, TUNEL apoptosis assay, CCl4 regeneration model Molecular and cellular biology High 19917719
2009 Direct interaction between dyskerin and human telomerase RNA (hTR) was demonstrated by single-molecule two-color coincidence detection. Deletion of hTR subdomains identified the RNA regions required for dyskerin binding. Dyskerin mutations associated with X-linked DC (but not hTR mutations associated with autosomal dominant DC) significantly impaired the dyskerin-hTR interaction. Single-molecule two-color coincidence detection (TCCD), systematic hTR subdomain deletions, recombinant dyskerin Biochemistry High 19835419
2010 Impaired DKC1 function causes a defect in IRES-mediated translation of p27 mRNA, reducing p27 protein and contributing to pituitary tumorigenesis in mice. DKC1 has a critical role in assembly of the 48S translational preinitiation complex mediated by the p27 IRES element. A somatic DKC1 mutation (S485G) found in a human pituitary adenoma alters DKC1 stability/pseudouridylation activity and reduces p27 levels without affecting telomerase RNA levels. Bioluminescent p27 IRES reporter mouse model, in vivo imaging, 48S preinitiation complex assembly assay, somatic mutation functional characterization Cancer research High 20587522
2010 siRNA-mediated reduction of dyskerin levels decreases p53 mRNA translation, protein levels, and functional activity in human breast cancer cells and primary mammary epithelial progenitor cells. This effect is associated with impairment of IRES-mediated translation of p53 mRNA and is independent of dyskerin's role in telomerase function. siRNA knockdown, polysome profiling, IRES reporter assay, p53 target gene expression analysis Cancer research Medium 20501855
2011 Crystal structure of Shq1-specific domain in complex with Cbf5, Nop10 and Gar1. Shq1 contacts the PUA domain and the C-terminal extension (CTE) of Cbf5. Shq1 binds Cbf5 independently of Nop10, Gar1, Nhp2 and Naf1, but shares an overlapping binding surface with H/ACA RNA. DC mutations in the CTE likely interfere with Shq1 binding. Shq1 functions as an assembly chaperone protecting Cbf5 from non-specific RNA binding before H/ACA RNA assembly. X-ray crystallography, yeast genetics (point mutations disrupting Cbf5-Shq1 interaction), binding competition assays The EMBO journal High 22117216
2011 Defects in dyskerin binding to hTR lead to hTR degradation via PAPD5-mediated oligoadenylation promoting 3'-to-5' degradation by EXOSC10 and 5'-to-3' decay by cytoplasmic DCP2 and XRN1. PARN increases hTR levels by deadenylating hTR, limiting EXOSC10-mediated degradation. Knockdown of DCP2 and/or EXOSC10 rescues telomerase activity and hTR localization in dyskerin-deficient cells. RNAi knockdown of decay factors, TRAP telomerase assay, hTR localization imaging, RNA decay analysis Nature structural & molecular biology High 26950371
2012 SMUG1 (single-strand-selective monofunctional uracil-DNA glycosylase 1) directly interacts with dyskerin (DKC1) and colocalizes with DKC1 in nucleoli and Cajal bodies. SMUG1 associates with the 47S rRNA precursor processed by DKC1. Combined depletion of SMUG1 and DKC1 leads to accumulation of 5-hydroxymethyluridine in rRNA. SMUG1 contributes to rRNA quality control partly by regulating 5-hydroxymethyluridine levels. Co-IP, colocalization imaging, RNA immunoprecipitation, siRNA depletion, mass spectrometry Molecular cell High 23246433
2012 Archaeal Nop10 and Gar1 both increase Cbf5's affinity for tRNA and directly enhance Cbf5's catalytic activity by increasing kcat of pseudouridylation. In contrast to guide RNA-dependent reaction, Gar1 is not involved in product release after tRNA modification in the guide-independent reaction. In vitro pseudouridylation kinetics assay with purified components (Cbf5, Nop10, Gar1), kcat/Km determination Scientific reports High 22993689
2013 Dyskerin SUMOylation is required for its stability; DC-causing mutations in highly conserved dyskerin SUMOylation consensus sites lead to impaired hTR accumulation, reduced telomerase activity and telomere maintenance defects. SUMO modification assay, telomerase activity (TRAP), telomere length measurement, stability assays with DC mutants Human molecular genetics Medium 23660516
2013 The A353V dyskerin mutation (most prevalent DC mutation) does not affect formation of the NAF1-dyskerin-NOP10-NHP2 tetramer but slightly reduces pre-RNP assembly with the H/ACA-like domain of hTR. NHP2 mutations V126M and Y139H impair NHP2-NOP10 association, causing major pre-RNP assembly defects with all H/ACA RNAs including hTR. Coimmunoprecipitation, H/ACA pre-RNP assembly assays with specific sno/scaRNAs and hTR H/ACA domain Human molecular genetics Medium 20008900
2013 Dyskerin redistributes from the nucleolus in interphase to the perichromosomal region during prometaphase, metaphase and anaphase, and to the cytoplasm within the mid-pole region during anaphase. Loss of dyskerin via siRNA promotes G2/M accumulation, increased mitotic index, spindle assembly checkpoint activation, multi-polar spindles, anaphase bridges and micronucleus formation. Immunofluorescence (cell cycle-staged), siRNA knockdown, live cell imaging, spindle assembly checkpoint markers PloS one Medium 24303026
2013 Dyskerin depletion causes a decrease in dyskerin knockdown cells that show altered translational fidelity and impaired IRES-mediated translation. Ribosomes purified from dyskerin-depleted human cells exhibit reduced rRNA pseudouridylation and altered synthetic activity in a cell-free translation system, with no difference in ribosomal protein composition. This establishes that rRNA pseudouridylation deficiency is sufficient to alter ribosome translational activity. siRNA knockdown, ribosome purification, cell-free translation assay (reticulocyte system), mass spectrometry of ribosomal proteins, pseudouridylation level analysis FASEB journal High 25934701
2013 Dyskerin depletion increases VEGF mRNA IRES-mediated translation, leading to increased VEGF protein production without significant upregulation of VEGF mRNA. This shows that dyskerin differentially affects IRES-mediated translation of different mRNAs (suppressing p27/p53 IRES but upregulating VEGF IRES). siRNA knockdown, bicistronic IRES reporter assays, ELISA for VEGF protein, RT-PCR for VEGF mRNA Nucleic acids research Medium 23821664
2013 Mouse embryonic fibroblasts expressing only catalytically inactive dyskerin (D125A) produce mature cytoplasmic rRNAs lacking pseudouridine that are very unstable, demonstrating that pseudouridine is required to stabilize rRNA secondary structure. Cells can divide very slowly without pseudouridine in rRNA, but show abnormalities in rRNA synthesis. Knock-in of catalytically inactive D125A mutant in MEFs, rRNA pseudouridylation assay, rRNA stability measurement FEBS letters High 23726835
2014 The dyskerin (DKC1) ribonucleoprotein complex was purified and identified as an OCT4/SOX2 coactivator in embryonic stem cells using a biochemically defined in vitro transcription system. The DKC1 complex occupies enhancers of key pluripotency genes, regulates their expression, and depletion of DKC1 in fibroblasts significantly decreases iPS cell reprogramming efficiency. This activity appears modulated by associated snoRNAs. Biochemical purification from in vitro transcription system, ChIP-seq, siRNA depletion, iPSC reprogramming efficiency assay eLife High 25407680
2016 SMN and coilin negatively regulate dyskerin association with telomerase RNA (hTR). Reduction of SMN or coilin is correlated with increased association of hTR with dyskerin. Clinically defined SMN mutants found in spinal muscular atrophy patients show altered association with telomerase complex proteins including dyskerin. Co-IP, siRNA knockdown of SMN and coilin, association assays with telomerase components Biology open Medium 27215323
2017 SHQ1 mutations that map to the SHQ1-NAP57/dyskerin interface impair the interaction between recombinant SHQ1 variants and NAP57 in pulldown assays, demonstrating that SHQ1 is an assembly factor for dyskerin-containing H/ACA RNPs. Pulldown assays with recombinant proteins, patient exome sequencing Molecular genetics & genomic medicine Medium 29178645
2019 N-terminal residues of dyskerin (K39E and K43E) are required for hTR binding. These N-terminal variants exhibit impaired binding to hTR and polyadenylated hTR species while interactions with other H/ACA RNAs are largely unperturbed. hTR accumulation and telomerase activity defects were rescued by wild-type but not variant dyskerin. hTR 3'-extended/polyadenylated species did not accumulate, suggesting hTR precursor degradation occurs upstream of mature complex assembly in the absence of dyskerin binding. Co-IP of dyskerin with hTR, rescue assays in dyskerin-deficient cells, TRAP telomerase assay Nucleic acids research High 30931479
2019 GATA1 transcriptionally regulates DKC1 in erythroid cells, as shown by ChIP and reporter assays. Upregulation of DKC1 during erythroid commitment drives increased telomerase activity in the presence of limiting TERT mRNA. DKC1 upregulation is necessary for expansion of glycophorin A+ erythroblasts and sufficient to extend telomeres in erythroleukemia cells. ChIP assay, luciferase reporter assay, siRNA knockdown, telomerase activity assay, telomere length measurement Haematologica Medium 31413099
2019 DKC1 facilitates colorectal cancer angiogenesis and metastasis by increasing HIF-1α and VEGF expression levels. Chromatin immunoprecipitation demonstrated that DKC1 promotes HIF-1α expression by directly regulating HIF-1α promoter activity. Chromatin immunoprecipitation (ChIP), in vitro and in vivo functional assays, siRNA knockdown, overexpression British journal of cancer Medium 31857720
2020 DKC1 mutation (E206K) and NOP10 mutation (T16Met) both fall at the dyskerin-NOP10 binding interface, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Patients show reduced pseudouridine levels in rRNA. Zebrafish dkc1 mutants show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. Structural analysis, interaction assays (dyskerin-NOP10), rRNA pseudouridylation quantification in patient cells, zebrafish loss-of-function model Proceedings of the National Academy of Sciences of the United States of America High 32554502
2021 DKC1 binds to and stabilizes the mRNAs of several ribosomal proteins (RPL10A, RPL22L1, RPL34, RPS3), as shown by RNA immunoprecipitation sequencing and RNA decay analysis. DKC1 depletion accelerates mRNA decay of these ribosomal proteins. Enforced expression of catalytically inactive DKC1 (D125A) does not accelerate cell growth, establishing the catalytic activity requirement. DKC1-regulated ribosomal proteins interact with HRAS and suppress the RAS/RAF/MEK/ERK pathway. Genome-wide RNAi screen, RIP-seq, RNA decay assays, catalytic mutant (D125A) overexpression, proteomics, xenograft mouse model Advanced science High 34026451
2021 SUMOylation of dyskerin at SUMO site K467 in the C-terminal nuclear/nucleolar localization signal (N/NoLS) is required for subnuclear localization to the nucleolus. Mimicking constitutive SUMOylation via SUMO3 fusion drives nuclear accumulation of a cytoplasmic C-terminal truncation variant. GAR1 contains a SUMO-interacting motif that mediates the dyskerin-GAR1 interaction. Mislocalization of dyskerin (cytoplasm or exclusion from nucleolus) disrupts dyskerin function and reduces dyskerin interaction with telomerase RNA. SUMO fusion constructs, subcellular fractionation, coimmunoprecipitation, telomerase RNA interaction assays, live-cell imaging Molecular and cellular biology High 33526451
2023 Dyskerin associates with RNA polymerase II, binds to thousands of mRNAs, and pseudouridylates them in chromatin in a guide RNA-independent manner. In cells lacking dyskerin, mRNA pseudouridylation is reduced while de novo protein synthesis is enhanced, indicating mRNA pseudouridylation by dyskerin inhibits translation. mRNAs with fewer pseudouridines due to dyskerin knockdown are translated more efficiently. mRNA pseudouridylation is severely reduced in dyskeratosis congenita patients with DKC1 mutations. RNA-seq, pseudouridine sequencing, co-IP with RNA Pol II, siRNA knockdown, de novo protein synthesis assay (SUnSET), polysome profiling, patient cells analysis Science advances High 37506213
2023 SENP3 interacts with DKC1 and catalyzes deSUMOylation of DKC1 at three lysine residues (SUMO3 modification sites), causing DKC1 instability and disrupting interaction between snoRNP proteins, leading to impaired migration of pancreatic ductal adenocarcinoma cells. Co-IP, SUMO modification assays, CRISPR/Cas9 knock-in, xenograft mouse model, in vitro invasion assays Cell death and differentiation High 37188742

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 NAP57, a mammalian nucleolar protein with a putative homolog in yeast and bacteria. The Journal of cell biology 222 7798307
1999 X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. American journal of human genetics 195 10364516
1999 Point mutations in yeast CBF5 can abolish in vivo pseudouridylation of rRNA. Molecular and cellular biology 191 10523634
1999 Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. British journal of haematology 176 10583221
2004 Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing. Proceedings of the National Academy of Sciences of the United States of America 151 15240872
2010 Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis. Cancer research 140 20587522
2006 Crystal structure of a Cbf5-Nop10-Gar1 complex and implications in RNA-guided pseudouridylation and dyskeratosis congenita. Molecular cell 134 16427014
2014 A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia. Chest 112 24504062
2016 Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects. Nature structural & molecular biology 103 26950371
2009 DKC1 overexpression associated with prostate cancer progression. British journal of cancer 98 19755982
2006 Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer. The Journal of pathology 96 16841302
2005 The Cbf5-Nop10 complex is a molecular bracket that organizes box H/ACA RNPs. Nature structural & molecular biology 94 16286935
2010 Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation. Cancer research 87 20501855
2013 Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. Human mutation 85 23946118
2021 Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 84 34026451
2002 Targeted disruption of Dkc1, the gene mutated in X-linked dyskeratosis congenita, causes embryonic lethality in mice. Oncogene 83 12400016
2021 Dyskerin: an essential pseudouridine synthase with multifaceted roles in ribosome biogenesis, splicing, and telomere maintenance. RNA (New York, N.Y.) 78 34556550
2008 A pathogenic dyskerin mutation impairs proliferation and activates a DNA damage response independent of telomere length in mice. Proceedings of the National Academy of Sciences of the United States of America 78 18626023
2019 DKC1 enhances angiogenesis by promoting HIF-1α transcription and facilitates metastasis in colorectal cancer. British journal of cancer 74 31857720
2001 Identification of novel DKC1 mutations in patients with dyskeratosis congenita: implications for pathophysiology and diagnosis. Human genetics 72 11379875
2000 A CBF5 mutation that disrupts nucleolar localization of early tRNA biosynthesis in yeast also suppresses tRNA gene-mediated transcriptional silencing. Proceedings of the National Academy of Sciences of the United States of America 63 11069303
2012 The human base excision repair enzyme SMUG1 directly interacts with DKC1 and contributes to RNA quality control. Molecular cell 62 23246433
1999 Dyskerin localizes to the nucleolus and its mislocalization is unlikely to play a role in the pathogenesis of dyskeratosis congenita. Human molecular genetics 62 10556300
2002 A novel DKC1 mutation, severe combined immunodeficiency (T+B-NK- SCID) and bone marrow transplantation in an infant with Hoyeraal-Hreidarsson syndrome. British journal of haematology 61 12437656
2015 Human ribosomes from cells with reduced dyskerin levels are intrinsically altered in translation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 58 25934701
2022 Sex differences in telomere length, lifespan, and embryonic dyskerin levels. Aging cell 54 35441417
2019 Increased DKC1 expression in glioma and its significance in tumor cell proliferation, migration and invasion. Investigational new drugs 50 30847721
2011 Decreased dyskerin levels as a mechanism of telomere shortening in X-linked dyskeratosis congenita. Journal of medical genetics 49 21415081
2009 Effects of dyskeratosis congenita mutations in dyskerin, NHP2 and NOP10 on assembly of H/ACA pre-RNPs. Human molecular genetics 49 20008900
2014 Human dyskerin: beyond telomeres. Biological chemistry 48 24468621
2013 Dyskerin depletion increases VEGF mRNA internal ribosome entry site-mediated translation. Nucleic acids research 48 23821664
2011 Structure of the Shq1-Cbf5-Nop10-Gar1 complex and implications for H/ACA RNP biogenesis and dyskeratosis congenita. The EMBO journal 47 22117216
2005 Elucidating the role of H/ACA-like RNAs in trans-splicing and rRNA processing via RNA interference silencing of the Trypanosoma brucei CBF5 pseudouridine synthase. The Journal of biological chemistry 47 16107339
2008 Relationship between dyskerin expression and telomerase activity in human breast cancer. Cellular oncology : the official journal of the International Society for Cellular Oncology 44 18936525
2020 Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis. Proceedings of the National Academy of Sciences of the United States of America 42 32554502
2014 The dyskerin ribonucleoprotein complex as an OCT4/SOX2 coactivator in embryonic stem cells. eLife 42 25407680
2009 Dyskerin ablation in mouse liver inhibits rRNA processing and cell division. Molecular and cellular biology 42 19917719
2020 CircMEG3 inhibits telomerase activity by reducing Cbf5 in human liver cancer stem cells. Molecular therapy. Nucleic acids 41 33425489
2010 Dyskerin is required for tumor cell growth through mechanisms that are independent of its role in telomerase and only partially related to its function in precursor rRNA processing. Molecular carcinogenesis 39 21480387
2022 Exosomes from human adipose-derived mesenchymal stromal/stem cells accelerate angiogenesis in wound healing: implication of the EGR-1/lncRNA-SENCR/DKC1/VEGF-A axis. Human cell 37 35751795
2016 MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin. Cancer research 37 27197171
2021 LncRNA PCAT1 Interacts with DKC1 to Regulate Proliferation, Invasion and Apoptosis in NSCLC Cells via the VEGF/AKT/Bcl2/Caspase9 Pathway. Cell transplantation 36 33461333
2020 LncRNA MEG3 inhibits non-small cell lung cancer via interaction with DKC1 protein. Oncology letters 36 32782535
2018 Oxidatively Modified Protein-Disulfide Isomerase-Associated 3 Promotes Dyskerin Pseudouridine Synthase 1-Mediated Malignancy and Survival of Hepatocellular Carcinoma Cells. Hepatology (Baltimore, Md.) 36 29672884
2020 Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis. Chest 35 32710892
2010 Dyskerin and cancer: more than telomerase. The defect in mRNA translation helps in explaining how a proliferative defect leads to cancer. The Journal of pathology 35 20925138
2021 Inhibition of DKC1 induces telomere-related senescence and apoptosis in lung adenocarcinoma. Journal of translational medicine 34 33879171
2014 Inhibition of human dyskerin as a new approach to target ribosome biogenesis. PloS one 33 25010840
2015 Dyskerin and TERC expression may condition survival in lung cancer patients. Oncotarget 31 26301749
2020 DKC1 Overexpression Induces a More Aggressive Cellular Behavior and Increases Intrinsic Ribosomal Activity in Immortalized Mammary Gland Cells. Cancers 30 33255756
2016 Investigation of chromosome X inactivation and clinical phenotypes in female carriers of DKC1 mutations. American journal of hematology 30 27570172
2012 Archaeal proteins Nop10 and Gar1 increase the catalytic activity of Cbf5 in pseudouridylating tRNA. Scientific reports 28 22993689
2007 DKC1 is a direct and conserved transcriptional target of c-MYC. Biochemical and biophysical research communications 28 17822678
2010 Correlation of dyskerin expression with active proliferation independent of telomerase. Head & neck 27 21674675
2009 Dyskerin, telomerase and the DNA damage response. Cell cycle (Georgetown, Tex.) 26 19106610
1995 Overexpression of the yeast MCK1 protein kinase suppresses conditional mutations in centromere-binding protein genes CBF2 and CBF5. Molecular & general genetics : MGG 26 7854321
2019 N-terminal residues of human dyskerin are required for interactions with telomerase RNA that prevent RNA degradation. Nucleic acids research 25 30931479
2016 SMN and coilin negatively regulate dyskerin association with telomerase RNA. Biology open 25 27215323
2023 Control of protein synthesis through mRNA pseudouridylation by dyskerin. Science advances 24 37506213
2007 A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells. Blood 24 18057229
2013 Dyskeratosis congenita mutations in dyskerin SUMOylation consensus sites lead to impaired telomerase RNA accumulation and telomere defects. Human molecular genetics 23 23660516
2005 Identification of DKC1 gene mutations in Japanese patients with X-linked dyskeratosis congenita. British journal of haematology 23 15842668
2023 SUMO specific peptidase 3 halts pancreatic ductal adenocarcinoma metastasis via deSUMOylating DKC1. Cell death and differentiation 22 37188742
2009 Single-molecule analysis of the human telomerase RNA.dyskerin interaction and the effect of dyskeratosis congenita mutations. Biochemistry 22 19835419
2001 One novel and two recurrent missense DKC1 mutations in patients with dyskeratosis congenita (DKC). Genetic counseling (Geneva, Switzerland) 22 11491307
2013 Severity of X-linked dyskeratosis congenita (DKCX) cellular defects is not directly related to dyskerin (DKC1) activity in ribosomal RNA biogenesis or mRNA translation. Human mutation 21 24115260
2012 High resolution melting analysis for the identification of novel mutations in DKC1 and TERT genes in patients with dyskeratosis congenita. Blood cells, molecules & diseases 21 22664374
2011 A new human dyskerin isoform with cytoplasmic localization. Biochimica et biophysica acta 21 21820037
2004 Identification of a novel mutation and a de novo mutation in DKC1 in two Chinese pedigrees with Dyskeratosis congenita. The Journal of investigative dermatology 21 15304085
2019 DKC1 is a transcriptional target of GATA1 and drives upregulation of telomerase activity in normal human erythroblasts. Haematologica 20 31413099
2018 Dyskeratosis congenita with a novel genetic variant in the DKC1 gene: a case report. BMC medical genetics 20 29801475
2020 Acute depletion of telomerase components DKC1 and NOP10 induces oxidative stress and disrupts ribosomal biogenesis via NPM1 and activation of the P53 pathway. Biochimica et biophysica acta. Molecular cell research 19 32910990
2002 A novel missense mutation in the DKC1 gene in a Japanese family with X-linked dyskeratosis congenita. Pediatric hematology and oncology 19 12186364
2018 Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment. International journal of molecular sciences 18 30340325
2013 DKC1 gene mutations in human sporadic cancer. Histology and histopathology 18 23348390
2000 Gene structure and expression of the mouse dyskeratosis congenita gene, dkc1. Genomics 18 10903840
1998 The lysine-rich C-terminal repeats of the centromere-binding factor 5 (Cbf5) of Kluyveromyces lactis are not essential for function. Yeast (Chichester, England) 18 9483794
2019 Telomere dynamics and hematopoietic differentiation of human DKC1-mutant induced pluripotent stem cells. Stem cell research 17 31479877
2017 Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita. Molecular genetics & genomic medicine 17 29178645
2013 A Novel Missense Mutation of DKC1 In Dyskeratosis Congenita With Pulmonary Fibrosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG 17 24284296
2014 Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis. Biochemical and biophysical research communications 16 24690175
2021 SUMOylation- and GAR1-Dependent Regulation of Dyskerin Nuclear and Subnuclear Localization. Molecular and cellular biology 15 33526451
2010 Structural and functional evidence of high specificity of Cbf5 for ACA trinucleotide. RNA (New York, N.Y.) 15 21149572
2022 UTP14A, DKC1, DDX10, PinX1, and ESF1 Modulate Cardiac Angiogenesis Leading to Obesity-Induced Cardiac Injury. Journal of diabetes research 14 35734237
2017 A functional connection between dyskerin and energy metabolism. Redox biology 14 29132127
2014 Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing. Gene 14 24914498
2013 Intron retention: a human DKC1 gene common splicing event. Biochemistry and cell biology = Biochimie et biologie cellulaire 14 24219293
1999 Analysis of epitope-tagged forms of the dyskeratosis congenital protein (dyskerin): identification of a nuclear localization signal. Blood cells, molecules & diseases 14 10744426
2013 Multiscale in situ analysis of the role of dyskerin in lung cancer cells. Integrative biology : quantitative biosciences from nano to macro 13 23233094
2012 Defects in mTR stability and telomerase activity produced by the Dkc1 A353V mutation in dyskeratosis congenita are rescued by a peptide from the dyskerin TruB domain. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 13 22855157
2022 Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence. Genome biology 12 35996163
2020 Successful liver transplantation in short telomere syndromes without bone marrow failure due to DKC1 mutation. Pediatric transplantation 12 32166868
2013 Slow growth and unstable ribosomal RNA lacking pseudouridine in mouse embryonic fibroblast cells expressing catalytically inactive dyskerin. FEBS letters 12 23726835
2011 Native gel electrophoresis of human telomerase distinguishes active complexes with or without dyskerin. Nucleic acids research 12 22187156
2020 CD8+ T-cell senescence and skewed lymphocyte subsets in young Dyskeratosis Congenita patients with PARN and DKC1 mutations. Journal of clinical laboratory analysis 11 32452087
2015 GSE4, a Small Dyskerin- and GSE24.2-Related Peptide, Induces Telomerase Activity, Cell Proliferation and Reduces DNA Damage, Oxidative Stress and Cell Senescence in Dyskerin Mutant Cells. PloS one 11 26571381
2008 Determination of protein-RNA interaction sites in the Cbf5-H/ACA guide RNA complex by mass spectrometric protein footprinting. Biochemistry 11 18205399
2018 Discovery of new chromen-4-one derivatives as telomerase inhibitors through regulating expression of dyskerin. Journal of enzyme inhibition and medicinal chemistry 10 30132373
2017 Drosophila dyskerin is required for somatic stem cell homeostasis. Scientific reports 10 28337032
2013 Dyskerin localizes to the mitotic apparatus and is required for orderly mitosis in human cells. PloS one 10 24303026

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