{"gene":"DKC1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1994,"finding":"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.","method":"Coimmunoprecipitation, immunofluorescence, immunogold electron microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP combined with two independent imaging methods (IF and immunogold EM) in a dedicated mechanistic study","pmids":["7798307"],"is_preprint":false},{"year":1999,"finding":"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.","method":"In vitro mutagenesis, in vivo pseudouridylation assay, growth phenotype analysis, snoRNA co-association assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis with functional pseudouridylation readout and snoRNA binding assay, multiple mutants tested","pmids":["10523634"],"is_preprint":false},{"year":1999,"finding":"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.","method":"EGFP fusion live-cell imaging, deletion/mutation analysis of NLS constructs, time-course expression in mammalian cell lines","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-cell imaging with systematic deletion mapping of NLS elements, multiple mutant constructs tested","pmids":["10556300"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Epitope-tagged transfection, immunofluorescence, deletion analysis, co-IP (negative result for FANCA interaction)","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, deletion mapping of NLS, but limited to single method per claim","pmids":["10744426"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Murine embryonic stem cell knock-in, TRAP telomerase assay, real-time PCR for snoRNAs and TERC, pseudouridylation assays, telomere length measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (knock-in mutant ES cells, TRAP, pseudouridylation, telomere length) in a single rigorous study","pmids":["15240872"],"is_preprint":false},{"year":2005,"finding":"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.","method":"X-ray crystallography, mutagenesis, cross-species assembly assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 1.95 Å with mutagenesis validation and cross-species functional assembly","pmids":["16286935"],"is_preprint":false},{"year":2006,"finding":"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.","method":"X-ray crystallography, structural modeling of full RNP complex with guide and substrate RNAs, mapping of DC mutations","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — 2.1 Å crystal structure with full RNP modeling and disease mutation mapping","pmids":["16427014"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Conditionally active c-MYC transgene system, chromatin immunoprecipitation (ChIP), RT-PCR, cycloheximide treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus conditional transgene with protein synthesis inhibition, single lab, two orthogonal methods","pmids":["17822678"],"is_preprint":false},{"year":2008,"finding":"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).","method":"Mouse knock-in model, X-inactivation pattern analysis (genetic epistasis), DNA damage foci immunofluorescence (co-localization with telomeres), etoposide treatment assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (telomerase dependence) combined with cellular imaging and DNA damage assays in a rigorous mouse model","pmids":["18626023"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Cre/loxP conditional knockout in mouse liver, Northern blot for rRNA precursors, immunofluorescence for fibrillarin, TUNEL apoptosis assay, CCl4 regeneration model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean tissue-specific KO with multiple orthogonal readouts (rRNA processing, nucleolar morphology, apoptosis, proliferation)","pmids":["19917719"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Single-molecule two-color coincidence detection (TCCD), systematic hTR subdomain deletions, recombinant dyskerin","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biophysical demonstration of protein-RNA interaction with mutagenesis mapping, single lab but rigorous method","pmids":["19835419"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Bioluminescent p27 IRES reporter mouse model, in vivo imaging, 48S preinitiation complex assembly assay, somatic mutation functional characterization","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including in vivo reporter, preinitiation complex assembly assay, and human tumor mutation functional validation","pmids":["20587522"],"is_preprint":false},{"year":2010,"finding":"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.","method":"siRNA knockdown, polysome profiling, IRES reporter assay, p53 target gene expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple readouts (polysome, IRES reporter, p53 targets), single lab","pmids":["20501855"],"is_preprint":false},{"year":2011,"finding":"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.","method":"X-ray crystallography, yeast genetics (point mutations disrupting Cbf5-Shq1 interaction), binding competition assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with genetic and biochemical validation of chaperone function","pmids":["22117216"],"is_preprint":false},{"year":2011,"finding":"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.","method":"RNAi knockdown of decay factors, TRAP telomerase assay, hTR localization imaging, RNA decay analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway placement by genetic rescue experiments with multiple decay pathway components, replicated across dyskerin- and PARN-deficient contexts","pmids":["26950371"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-IP, colocalization imaging, RNA immunoprecipitation, siRNA depletion, mass spectrometry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, colocalization, RIP, and functional depletion studies with multiple orthogonal methods","pmids":["23246433"],"is_preprint":false},{"year":2012,"finding":"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.","method":"In vitro pseudouridylation kinetics assay with purified components (Cbf5, Nop10, Gar1), kcat/Km determination","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro enzymatic assay with kinetic parameters, single lab","pmids":["22993689"],"is_preprint":false},{"year":2013,"finding":"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.","method":"SUMO modification assay, telomerase activity (TRAP), telomere length measurement, stability assays with DC mutants","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM identification with functional consequences on telomerase RNA and telomere maintenance, single lab","pmids":["23660516"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Coimmunoprecipitation, H/ACA pre-RNP assembly assays with specific sno/scaRNAs and hTR H/ACA domain","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and assembly assays with multiple H/ACA RNAs and mutants, single lab","pmids":["20008900"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Immunofluorescence (cell cycle-staged), siRNA knockdown, live cell imaging, spindle assembly checkpoint markers","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization imaging across cell cycle stages plus loss-of-function with multiple mitotic phenotype readouts, single lab","pmids":["24303026"],"is_preprint":false},{"year":2013,"finding":"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.","method":"siRNA knockdown, ribosome purification, cell-free translation assay (reticulocyte system), mass spectrometry of ribosomal proteins, pseudouridylation level analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified ribosomes reconstituted in cell-free system, mass spectrometry, and pseudouridylation analysis provide mechanistic link","pmids":["25934701"],"is_preprint":false},{"year":2013,"finding":"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).","method":"siRNA knockdown, bicistronic IRES reporter assays, ELISA for VEGF protein, RT-PCR for VEGF mRNA","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IRES reporter assay with protein/mRNA quantification, single lab, two orthogonal methods","pmids":["23821664"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Knock-in of catalytically inactive D125A mutant in MEFs, rRNA pseudouridylation assay, rRNA stability measurement","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — catalytic dead knock-in with direct rRNA pseudouridylation and stability measurements, single lab","pmids":["23726835"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Biochemical purification from in vitro transcription system, ChIP-seq, siRNA depletion, iPSC reprogramming efficiency assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — purification from defined in vitro system combined with ChIP-seq and functional depletion, multiple orthogonal methods","pmids":["25407680"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-IP, siRNA knockdown of SMN and coilin, association assays with telomerase components","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and KD with multiple telomerase components, single lab","pmids":["27215323"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Pulldown assays with recombinant proteins, patient exome sequencing","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pulldown with recombinant proteins, single lab, single method","pmids":["29178645"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-IP of dyskerin with hTR, rescue assays in dyskerin-deficient cells, TRAP telomerase assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping by mutation with multiple functional assays (binding, rescue of RNA accumulation, telomerase activity), single lab with orthogonal methods","pmids":["30931479"],"is_preprint":false},{"year":2019,"finding":"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.","method":"ChIP assay, luciferase reporter assay, siRNA knockdown, telomerase activity assay, telomere length measurement","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus KD with telomere functional readout, single lab","pmids":["31413099"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Chromatin immunoprecipitation (ChIP), in vitro and in vivo functional assays, siRNA knockdown, overexpression","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus gain/loss-of-function with angiogenesis readout, single lab","pmids":["31857720"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Structural analysis, interaction assays (dyskerin-NOP10), rRNA pseudouridylation quantification in patient cells, zebrafish loss-of-function model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (structural mapping, interaction assay, patient rRNA analysis, zebrafish model) across two pedigrees","pmids":["32554502"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Genome-wide RNAi screen, RIP-seq, RNA decay assays, catalytic mutant (D125A) overexpression, proteomics, xenograft mouse model","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — RIP-seq plus RNA decay plus genetic rescue with catalytic mutant plus proteomics pathway analysis, multiple orthogonal methods","pmids":["34026451"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SUMO fusion constructs, subcellular fractionation, coimmunoprecipitation, telomerase RNA interaction assays, live-cell imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — SUMO fusion rescue, Co-IP, localization imaging, and telomerase RNA binding assays, multiple orthogonal methods in one study","pmids":["33526451"],"is_preprint":false},{"year":2023,"finding":"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.","method":"RNA-seq, pseudouridine sequencing, co-IP with RNA Pol II, siRNA knockdown, de novo protein synthesis assay (SUnSET), polysome profiling, patient cells analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — transcriptome-wide pseudouridine mapping combined with co-IP, de novo protein synthesis and polysome profiling, replicated in patient cells","pmids":["37506213"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP, SUMO modification assays, CRISPR/Cas9 knock-in, xenograft mouse model, in vitro invasion assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, SUMO modification mapping, CRISPR knock-in, and in vivo validation, multiple orthogonal methods","pmids":["37188742"],"is_preprint":false}],"current_model":"Dyskerin (DKC1) is the catalytic pseudouridine synthase subunit of H/ACA small nucleolar ribonucleoprotein (snoRNP) complexes, which it forms with NOP10, NHP2 (Nhp2), and GAR1 under the chaperone guidance of SHQ1; it converts specific uridines to pseudouridines in rRNA, snRNA, and mRNAs (the last in a guide RNA-independent, cotranscriptional manner that suppresses translation), and these pseudouridylation activities require an intact catalytic aspartate (D95 in yeast Cbf5; D125 in mouse). Dyskerin is also an obligate component of the human telomerase holoenzyme, binding directly to the H/ACA motif of hTR through its PUA domain and N-terminal residues to prevent oligoadenylation and EXOSC10/DCP2-XRN1-mediated degradation of hTR; SUMOylation at C-terminal lysine residues (especially K467) regulates its nuclear and nucleolar localization, which is essential for both its H/ACA RNP and telomerase functions. DKC1 is a direct transcriptional target of c-MYC and GATA1, and the DKC1 RNP complex can also act as an OCT4/SOX2 coactivator at enhancers of pluripotency genes; loss of dyskerin function reduces IRES-mediated translation of tumor suppressors (p27, p53) while paradoxically increasing IRES-mediated translation of VEGF, and selectively stabilizes mRNAs of ribosomal proteins that in turn suppress RAS/RAF/MEK/ERK signaling."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1994,"claim":"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","pmids":["7798307"],"confidence":"High","gaps":["Did not define an enzymatic activity","Functional consequence of the Nopp140 association unresolved"]},{"year":1999,"claim":"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","pmids":["10523634"],"confidence":"High","gaps":["Did not address telomerase role","Mechanism of guide RNA selection not resolved"]},{"year":1999,"claim":"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","pmids":["10556300","10744426"],"confidence":"High","gaps":["Did not link localization to catalytic or telomerase output","Regulation of trafficking unaddressed"]},{"year":2004,"claim":"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","pmids":["15240872"],"confidence":"High","gaps":["Structural basis of mutation-specific effects not defined","Did not resolve which defect drives disease"]},{"year":2005,"claim":"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","pmids":["16286935"],"confidence":"High","gaps":["Full RNP with guide and substrate not yet captured","Human dyskerin structure inferred from archaeal ortholog"]},{"year":2006,"claim":"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","pmids":["16427014"],"confidence":"High","gaps":["Telomerase-specific RNP architecture not addressed","Catalytic kinetics of cofactors not quantified here"]},{"year":2007,"claim":"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","pmids":["17822678"],"confidence":"Medium","gaps":["Single lab","Downstream functional consequence of MYC-driven DKC1 not tested here"]},{"year":2008,"claim":"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","pmids":["18626023"],"confidence":"High","gaps":["Molecular trigger of telomere-localized damage unresolved","Relationship to pseudouridylation defect not separated"]},{"year":2009,"claim":"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","pmids":["19917719","19835419"],"confidence":"High","gaps":["hTR-binding determinants on dyskerin not fully mapped at residue level","Did not resolve how hTR escapes degradation"]},{"year":2010,"claim":"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","pmids":["20587522","20501855"],"confidence":"High","gaps":["Direct molecular basis of IRES selectivity unresolved","p53 effect shown by siRNA in single lab"]},{"year":2011,"claim":"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","pmids":["22117216"],"confidence":"High","gaps":["Hand-off mechanism from SHQ1 to H/ACA RNA not kinetically resolved","Human SHQ1-dyskerin interface inferred"]},{"year":2011,"claim":"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)","pmids":["26950371"],"confidence":"High","gaps":["Precise recognition step distinguishing protected vs degraded hTR not defined"]},{"year":2012,"claim":"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","pmids":["23246433","22993689"],"confidence":"High","gaps":["Functional importance of SMUG1 partnership in disease unclear","Kinetics measured on archaeal components and tRNA substrate"]},{"year":2013,"claim":"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","pmids":["23726835","20008900","23660516","24303026","23821664","25934701"],"confidence":"High","gaps":["Mechanism of opposite IRES effects (VEGF up vs p27/p53 down) unresolved","Mitotic and SUMO findings from single labs"]},{"year":2014,"claim":"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","pmids":["25407680"],"confidence":"High","gaps":["How snoRNAs modulate the coactivator activity not mechanistically defined","Whether catalysis is required unresolved"]},{"year":2016,"claim":"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","pmids":["27215323"],"confidence":"Medium","gaps":["Single lab","Direct vs indirect regulation not distinguished"]},{"year":2019,"claim":"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","pmids":["30931479","31413099","31857720"],"confidence":"High","gaps":["Erythroid and cancer ChIP findings from single labs","Whether DKC1 directly binds HIF-1α promoter vs acts via cofactor unresolved"]},{"year":2020,"claim":"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","pmids":["32554502"],"confidence":"High","gaps":["Tissue-specific consequences of ribosomal dysregulation not fully defined"]},{"year":2021,"claim":"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","pmids":["34026451","33526451"],"confidence":"High","gaps":["Mechanism by which DKC1 selects/stabilizes specific ribosomal-protein mRNAs unresolved","Link between mRNA stabilization and pseudouridylation catalysis not directly shown"]},{"year":2023,"claim":"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","pmids":["37506213","37188742"],"confidence":"High","gaps":["How dyskerin selects mRNA target sites without guide RNA unresolved","Physiological scope of translational suppression across cell types unclear"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,4,16,20,22,29,32]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10,14,26,30,32]},{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[1,22,29]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[23,28]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[11,12,20,21,32]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,2,9,15,31]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,31]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,9,22,32]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,19,29]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,12,20,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,23,27,28]}],"complexes":["H/ACA snoRNP","telomerase holoenzyme"],"partners":["NOP10","GAR1","NHP2","NAF1","SHQ1","HTR/TERC","SMUG1","NOPP140"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60832","full_name":"H/ACA ribonucleoprotein complex subunit DKC1","aliases":["CBF5 homolog","Dyskerin","Nopp140-associated protein of 57 kDa","Nucleolar protein NAP57","Nucleolar protein family A member 4","snoRNP protein DKC1"],"length_aa":514,"mass_kda":57.7,"function":"Catalytic subunit of H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA (PubMed:25219674, PubMed:32554502). This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1 (PubMed:25219674). Each rRNA can contain up to 100 pseudouridine ('psi') residues, which may serve to stabilize the conformation of rRNAs. Required for ribosome biogenesis and telomere maintenance (PubMed:19179534, PubMed:25219674). Also required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme (PubMed:19179534) Promotes cell to cell and cell to substratum adhesion, increases the cell proliferation rate and leads to cytokeratin hyper-expression","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O60832/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DKC1","classification":"Common Essential","n_dependent_lines":1174,"n_total_lines":1208,"dependency_fraction":0.9718543046357616},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000130826","cell_line_id":"CID001049","localizations":[{"compartment":"nucleolus_fc_dfc","grade":3}],"interactors":[{"gene":"SSRP1","stoichiometry":10.0},{"gene":"NOP10","stoichiometry":10.0},{"gene":"ARGLU1","stoichiometry":10.0},{"gene":"RBM17","stoichiometry":10.0},{"gene":"RSRC1","stoichiometry":10.0},{"gene":"NAF1","stoichiometry":10.0},{"gene":"SRSF6","stoichiometry":10.0},{"gene":"SUB1","stoichiometry":10.0},{"gene":"U2SURP","stoichiometry":10.0},{"gene":"SUPT16H","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001049","total_profiled":1310},"omim":[{"mim_id":"620425","title":"CATARACTS, HEARING IMPAIRMENT, NEPHROTIC SYNDROME, AND ENTEROCOLITIS 2; CHINE2","url":"https://www.omim.org/entry/620425"},{"mim_id":"620400","title":"PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 9; PFBMFT9","url":"https://www.omim.org/entry/620400"},{"mim_id":"619922","title":"NEURODEVELOPMENTAL DISORDER WITH DYSTONIA AND SEIZURES; NEDDS","url":"https://www.omim.org/entry/619922"},{"mim_id":"619921","title":"DYSTONIA 35, CHILDHOOD-ONSET; DYT35","url":"https://www.omim.org/entry/619921"},{"mim_id":"614742","title":"PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 1; PFBMFT1","url":"https://www.omim.org/entry/614742"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli fibrillar center","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DKC1"},"hgnc":{"alias_symbol":["XAP101","dyskerin","NAP57","NOLA4","Cbf5"],"prev_symbol":["DKC"]},"alphafold":{"accession":"O60832","domains":[{"cath_id":"3.30.2350.10","chopping":"91-256","consensus_level":"medium","plddt":95.2954,"start":91,"end":256},{"cath_id":"2.30.130.10","chopping":"297-370","consensus_level":"high","plddt":95.0768,"start":297,"end":370},{"cath_id":"-","chopping":"385-420","consensus_level":"high","plddt":80.1506,"start":385,"end":420}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60832","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60832-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60832-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DKC1","jax_strain_url":"https://www.jax.org/strain/search?query=DKC1"},"sequence":{"accession":"O60832","fasta_url":"https://rest.uniprot.org/uniprotkb/O60832.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60832/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60832"}},"corpus_meta":[{"pmid":"7798307","id":"PMC_7798307","title":"NAP57, a mammalian nucleolar protein with a putative homolog in yeast and bacteria.","date":"1994","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7798307","citation_count":222,"is_preprint":false},{"pmid":"10364516","id":"PMC_10364516","title":"X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene.","date":"1999","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10364516","citation_count":195,"is_preprint":false},{"pmid":"10523634","id":"PMC_10523634","title":"Point mutations in yeast CBF5 can abolish in vivo pseudouridylation of rRNA.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10523634","citation_count":191,"is_preprint":false},{"pmid":"10583221","id":"PMC_10583221","title":"Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1.","date":"1999","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/10583221","citation_count":176,"is_preprint":false},{"pmid":"15240872","id":"PMC_15240872","title":"Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15240872","citation_count":151,"is_preprint":false},{"pmid":"20587522","id":"PMC_20587522","title":"Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20587522","citation_count":140,"is_preprint":false},{"pmid":"16427014","id":"PMC_16427014","title":"Crystal structure of a Cbf5-Nop10-Gar1 complex and implications in RNA-guided pseudouridylation and dyskeratosis congenita.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16427014","citation_count":134,"is_preprint":false},{"pmid":"24504062","id":"PMC_24504062","title":"A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia.","date":"2014","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/24504062","citation_count":112,"is_preprint":false},{"pmid":"26950371","id":"PMC_26950371","title":"Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects.","date":"2016","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26950371","citation_count":103,"is_preprint":false},{"pmid":"19755982","id":"PMC_19755982","title":"DKC1 overexpression associated with prostate cancer progression.","date":"2009","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19755982","citation_count":98,"is_preprint":false},{"pmid":"16841302","id":"PMC_16841302","title":"Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer.","date":"2006","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16841302","citation_count":96,"is_preprint":false},{"pmid":"16286935","id":"PMC_16286935","title":"The Cbf5-Nop10 complex is a molecular bracket that organizes box H/ACA RNPs.","date":"2005","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16286935","citation_count":94,"is_preprint":false},{"pmid":"20501855","id":"PMC_20501855","title":"Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20501855","citation_count":87,"is_preprint":false},{"pmid":"23946118","id":"PMC_23946118","title":"Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene.","date":"2013","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/23946118","citation_count":85,"is_preprint":false},{"pmid":"34026451","id":"PMC_34026451","title":"Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells.","date":"2021","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/34026451","citation_count":84,"is_preprint":false},{"pmid":"12400016","id":"PMC_12400016","title":"Targeted disruption of Dkc1, the gene mutated in X-linked dyskeratosis congenita, causes embryonic lethality in mice.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12400016","citation_count":83,"is_preprint":false},{"pmid":"34556550","id":"PMC_34556550","title":"Dyskerin: an essential pseudouridine synthase with multifaceted roles in ribosome biogenesis, splicing, and telomere maintenance.","date":"2021","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/34556550","citation_count":78,"is_preprint":false},{"pmid":"18626023","id":"PMC_18626023","title":"A pathogenic dyskerin mutation impairs proliferation and activates a DNA damage response independent of telomere length in mice.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18626023","citation_count":78,"is_preprint":false},{"pmid":"31857720","id":"PMC_31857720","title":"DKC1 enhances angiogenesis by promoting HIF-1α transcription and facilitates metastasis in colorectal cancer.","date":"2019","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31857720","citation_count":74,"is_preprint":false},{"pmid":"11379875","id":"PMC_11379875","title":"Identification of novel DKC1 mutations in patients with dyskeratosis congenita: implications for pathophysiology and diagnosis.","date":"2001","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11379875","citation_count":72,"is_preprint":false},{"pmid":"11069303","id":"PMC_11069303","title":"A CBF5 mutation that disrupts nucleolar localization of early tRNA biosynthesis in yeast also suppresses tRNA gene-mediated transcriptional silencing.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11069303","citation_count":63,"is_preprint":false},{"pmid":"10556300","id":"PMC_10556300","title":"Dyskerin localizes to the nucleolus and its mislocalization is unlikely to play a role in the pathogenesis of dyskeratosis congenita.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10556300","citation_count":62,"is_preprint":false},{"pmid":"23246433","id":"PMC_23246433","title":"The human base excision repair enzyme SMUG1 directly interacts with DKC1 and contributes to RNA quality control.","date":"2012","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23246433","citation_count":62,"is_preprint":false},{"pmid":"12437656","id":"PMC_12437656","title":"A novel DKC1 mutation, severe combined immunodeficiency (T+B-NK- SCID) and bone marrow transplantation in an infant with Hoyeraal-Hreidarsson syndrome.","date":"2002","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/12437656","citation_count":61,"is_preprint":false},{"pmid":"25934701","id":"PMC_25934701","title":"Human ribosomes from cells with reduced dyskerin levels are intrinsically altered in translation.","date":"2015","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/25934701","citation_count":58,"is_preprint":false},{"pmid":"35441417","id":"PMC_35441417","title":"Sex differences in telomere length, lifespan, and embryonic dyskerin levels.","date":"2022","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/35441417","citation_count":54,"is_preprint":false},{"pmid":"30847721","id":"PMC_30847721","title":"Increased DKC1 expression in glioma and its significance in tumor cell proliferation, migration and invasion.","date":"2019","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/30847721","citation_count":50,"is_preprint":false},{"pmid":"21415081","id":"PMC_21415081","title":"Decreased dyskerin levels as a mechanism of telomere shortening in X-linked dyskeratosis congenita.","date":"2011","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21415081","citation_count":49,"is_preprint":false},{"pmid":"20008900","id":"PMC_20008900","title":"Effects of dyskeratosis congenita mutations in dyskerin, NHP2 and NOP10 on assembly of H/ACA pre-RNPs.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20008900","citation_count":49,"is_preprint":false},{"pmid":"24468621","id":"PMC_24468621","title":"Human dyskerin: beyond telomeres.","date":"2014","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24468621","citation_count":48,"is_preprint":false},{"pmid":"23821664","id":"PMC_23821664","title":"Dyskerin depletion increases VEGF mRNA internal ribosome entry site-mediated translation.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23821664","citation_count":48,"is_preprint":false},{"pmid":"22117216","id":"PMC_22117216","title":"Structure of the Shq1-Cbf5-Nop10-Gar1 complex and implications for H/ACA RNP biogenesis and dyskeratosis congenita.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22117216","citation_count":47,"is_preprint":false},{"pmid":"16107339","id":"PMC_16107339","title":"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.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16107339","citation_count":47,"is_preprint":false},{"pmid":"18936525","id":"PMC_18936525","title":"Relationship between dyskerin expression and telomerase activity in human breast cancer.","date":"2008","source":"Cellular oncology : the official journal of the International Society for Cellular Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18936525","citation_count":44,"is_preprint":false},{"pmid":"19917719","id":"PMC_19917719","title":"Dyskerin ablation in mouse liver inhibits rRNA processing and cell division.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19917719","citation_count":42,"is_preprint":false},{"pmid":"32554502","id":"PMC_32554502","title":"Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32554502","citation_count":42,"is_preprint":false},{"pmid":"25407680","id":"PMC_25407680","title":"The dyskerin ribonucleoprotein complex as an OCT4/SOX2 coactivator in embryonic stem cells.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25407680","citation_count":42,"is_preprint":false},{"pmid":"33425489","id":"PMC_33425489","title":"CircMEG3 inhibits telomerase activity by reducing Cbf5 in human liver cancer stem cells.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/33425489","citation_count":41,"is_preprint":false},{"pmid":"21480387","id":"PMC_21480387","title":"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.","date":"2010","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/21480387","citation_count":39,"is_preprint":false},{"pmid":"27197171","id":"PMC_27197171","title":"MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27197171","citation_count":37,"is_preprint":false},{"pmid":"35751795","id":"PMC_35751795","title":"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.","date":"2022","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/35751795","citation_count":37,"is_preprint":false},{"pmid":"33461333","id":"PMC_33461333","title":"LncRNA PCAT1 Interacts with DKC1 to Regulate Proliferation, Invasion and Apoptosis in NSCLC Cells via the VEGF/AKT/Bcl2/Caspase9 Pathway.","date":"2021","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/33461333","citation_count":36,"is_preprint":false},{"pmid":"32782535","id":"PMC_32782535","title":"LncRNA MEG3 inhibits non-small cell lung cancer via interaction with DKC1 protein.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32782535","citation_count":36,"is_preprint":false},{"pmid":"29672884","id":"PMC_29672884","title":"Oxidatively Modified Protein-Disulfide Isomerase-Associated 3 Promotes Dyskerin Pseudouridine Synthase 1-Mediated Malignancy and Survival of Hepatocellular Carcinoma Cells.","date":"2018","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/29672884","citation_count":36,"is_preprint":false},{"pmid":"32710892","id":"PMC_32710892","title":"Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis.","date":"2020","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/32710892","citation_count":35,"is_preprint":false},{"pmid":"20925138","id":"PMC_20925138","title":"Dyskerin and cancer: more than telomerase. The defect in mRNA translation helps in explaining how a proliferative defect leads to cancer.","date":"2010","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20925138","citation_count":35,"is_preprint":false},{"pmid":"33879171","id":"PMC_33879171","title":"Inhibition of DKC1 induces telomere-related senescence and apoptosis in lung adenocarcinoma.","date":"2021","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33879171","citation_count":34,"is_preprint":false},{"pmid":"25010840","id":"PMC_25010840","title":"Inhibition of human dyskerin as a new approach to target ribosome biogenesis.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25010840","citation_count":33,"is_preprint":false},{"pmid":"26301749","id":"PMC_26301749","title":"Dyskerin and TERC expression may condition survival in lung cancer patients.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26301749","citation_count":31,"is_preprint":false},{"pmid":"27570172","id":"PMC_27570172","title":"Investigation of chromosome X inactivation and clinical phenotypes in female carriers of DKC1 mutations.","date":"2016","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/27570172","citation_count":30,"is_preprint":false},{"pmid":"33255756","id":"PMC_33255756","title":"DKC1 Overexpression Induces a More Aggressive Cellular Behavior and Increases Intrinsic Ribosomal Activity in Immortalized Mammary Gland Cells.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33255756","citation_count":30,"is_preprint":false},{"pmid":"22993689","id":"PMC_22993689","title":"Archaeal proteins Nop10 and Gar1 increase the catalytic activity of Cbf5 in pseudouridylating tRNA.","date":"2012","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/22993689","citation_count":28,"is_preprint":false},{"pmid":"17822678","id":"PMC_17822678","title":"DKC1 is a direct and conserved transcriptional target of c-MYC.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17822678","citation_count":28,"is_preprint":false},{"pmid":"21674675","id":"PMC_21674675","title":"Correlation of dyskerin expression with active proliferation independent of telomerase.","date":"2010","source":"Head & neck","url":"https://pubmed.ncbi.nlm.nih.gov/21674675","citation_count":27,"is_preprint":false},{"pmid":"19106610","id":"PMC_19106610","title":"Dyskerin, telomerase and the DNA damage response.","date":"2009","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19106610","citation_count":26,"is_preprint":false},{"pmid":"7854321","id":"PMC_7854321","title":"Overexpression of the yeast MCK1 protein kinase suppresses conditional mutations in centromere-binding protein genes CBF2 and CBF5.","date":"1995","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/7854321","citation_count":26,"is_preprint":false},{"pmid":"27215323","id":"PMC_27215323","title":"SMN and coilin negatively regulate dyskerin association with telomerase RNA.","date":"2016","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/27215323","citation_count":25,"is_preprint":false},{"pmid":"30931479","id":"PMC_30931479","title":"N-terminal residues of human dyskerin are required for interactions with telomerase RNA that prevent RNA degradation.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/30931479","citation_count":25,"is_preprint":false},{"pmid":"37506213","id":"PMC_37506213","title":"Control of protein synthesis through mRNA pseudouridylation by dyskerin.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37506213","citation_count":24,"is_preprint":false},{"pmid":"18057229","id":"PMC_18057229","title":"A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18057229","citation_count":24,"is_preprint":false},{"pmid":"23660516","id":"PMC_23660516","title":"Dyskeratosis congenita mutations in dyskerin SUMOylation consensus sites lead to impaired telomerase RNA accumulation and telomere defects.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23660516","citation_count":23,"is_preprint":false},{"pmid":"15842668","id":"PMC_15842668","title":"Identification of DKC1 gene mutations in Japanese patients with X-linked dyskeratosis congenita.","date":"2005","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/15842668","citation_count":23,"is_preprint":false},{"pmid":"37188742","id":"PMC_37188742","title":"SUMO specific peptidase 3 halts pancreatic ductal adenocarcinoma metastasis via deSUMOylating DKC1.","date":"2023","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/37188742","citation_count":22,"is_preprint":false},{"pmid":"19835419","id":"PMC_19835419","title":"Single-molecule analysis of the human telomerase RNA.dyskerin interaction and the effect of dyskeratosis congenita mutations.","date":"2009","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19835419","citation_count":22,"is_preprint":false},{"pmid":"11491307","id":"PMC_11491307","title":"One novel and two recurrent missense DKC1 mutations in patients with dyskeratosis congenita (DKC).","date":"2001","source":"Genetic counseling (Geneva, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/11491307","citation_count":22,"is_preprint":false},{"pmid":"24115260","id":"PMC_24115260","title":"Severity of X-linked dyskeratosis congenita (DKCX) cellular defects is not directly related to dyskerin (DKC1) activity in ribosomal RNA biogenesis or mRNA translation.","date":"2013","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/24115260","citation_count":21,"is_preprint":false},{"pmid":"21820037","id":"PMC_21820037","title":"A new human dyskerin isoform with cytoplasmic localization.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21820037","citation_count":21,"is_preprint":false},{"pmid":"15304085","id":"PMC_15304085","title":"Identification of a novel mutation and a de novo mutation in DKC1 in two Chinese pedigrees with Dyskeratosis congenita.","date":"2004","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15304085","citation_count":21,"is_preprint":false},{"pmid":"22664374","id":"PMC_22664374","title":"High resolution melting analysis for the identification of novel mutations in DKC1 and TERT genes in patients with dyskeratosis congenita.","date":"2012","source":"Blood cells, molecules & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22664374","citation_count":21,"is_preprint":false},{"pmid":"31413099","id":"PMC_31413099","title":"DKC1 is a transcriptional target of GATA1 and drives upregulation of telomerase activity in normal human erythroblasts.","date":"2019","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/31413099","citation_count":20,"is_preprint":false},{"pmid":"29801475","id":"PMC_29801475","title":"Dyskeratosis congenita with a novel genetic variant in the DKC1 gene: a case report.","date":"2018","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29801475","citation_count":20,"is_preprint":false},{"pmid":"32910990","id":"PMC_32910990","title":"Acute depletion of telomerase components DKC1 and NOP10 induces oxidative stress and disrupts ribosomal biogenesis via NPM1 and activation of the P53 pathway.","date":"2020","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32910990","citation_count":19,"is_preprint":false},{"pmid":"12186364","id":"PMC_12186364","title":"A novel missense mutation in the DKC1 gene in a Japanese family with X-linked dyskeratosis congenita.","date":"2002","source":"Pediatric hematology and oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12186364","citation_count":19,"is_preprint":false},{"pmid":"10903840","id":"PMC_10903840","title":"Gene structure and expression of the mouse dyskeratosis congenita gene, dkc1.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10903840","citation_count":18,"is_preprint":false},{"pmid":"23348390","id":"PMC_23348390","title":"DKC1 gene mutations in human sporadic cancer.","date":"2013","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/23348390","citation_count":18,"is_preprint":false},{"pmid":"9483794","id":"PMC_9483794","title":"The lysine-rich C-terminal repeats of the centromere-binding factor 5 (Cbf5) of Kluyveromyces lactis are not essential for function.","date":"1998","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9483794","citation_count":18,"is_preprint":false},{"pmid":"30340325","id":"PMC_30340325","title":"Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30340325","citation_count":18,"is_preprint":false},{"pmid":"31479877","id":"PMC_31479877","title":"Telomere dynamics and hematopoietic differentiation of human DKC1-mutant induced pluripotent stem cells.","date":"2019","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31479877","citation_count":17,"is_preprint":false},{"pmid":"29178645","id":"PMC_29178645","title":"Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita.","date":"2017","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29178645","citation_count":17,"is_preprint":false},{"pmid":"24284296","id":"PMC_24284296","title":"A Novel Missense Mutation of DKC1 In Dyskeratosis Congenita With Pulmonary Fibrosis.","date":"2013","source":"Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG","url":"https://pubmed.ncbi.nlm.nih.gov/24284296","citation_count":17,"is_preprint":false},{"pmid":"24690175","id":"PMC_24690175","title":"Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24690175","citation_count":16,"is_preprint":false},{"pmid":"33526451","id":"PMC_33526451","title":"SUMOylation- and GAR1-Dependent Regulation of Dyskerin Nuclear and Subnuclear Localization.","date":"2021","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33526451","citation_count":15,"is_preprint":false},{"pmid":"21149572","id":"PMC_21149572","title":"Structural and functional evidence of high specificity of Cbf5 for ACA trinucleotide.","date":"2010","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21149572","citation_count":15,"is_preprint":false},{"pmid":"29132127","id":"PMC_29132127","title":"A functional connection between dyskerin and energy metabolism.","date":"2017","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/29132127","citation_count":14,"is_preprint":false},{"pmid":"35734237","id":"PMC_35734237","title":"UTP14A, DKC1, DDX10, PinX1, and ESF1 Modulate Cardiac Angiogenesis Leading to Obesity-Induced Cardiac Injury.","date":"2022","source":"Journal of diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/35734237","citation_count":14,"is_preprint":false},{"pmid":"24219293","id":"PMC_24219293","title":"Intron retention: a human DKC1 gene common splicing event.","date":"2013","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/24219293","citation_count":14,"is_preprint":false},{"pmid":"24914498","id":"PMC_24914498","title":"Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24914498","citation_count":14,"is_preprint":false},{"pmid":"10744426","id":"PMC_10744426","title":"Analysis of epitope-tagged forms of the dyskeratosis congenital protein (dyskerin): identification of a nuclear localization signal.","date":"1999","source":"Blood cells, molecules & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/10744426","citation_count":14,"is_preprint":false},{"pmid":"22855157","id":"PMC_22855157","title":"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.","date":"2012","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/22855157","citation_count":13,"is_preprint":false},{"pmid":"23233094","id":"PMC_23233094","title":"Multiscale in situ analysis of the role of dyskerin in lung cancer cells.","date":"2013","source":"Integrative biology : quantitative biosciences from nano to macro","url":"https://pubmed.ncbi.nlm.nih.gov/23233094","citation_count":13,"is_preprint":false},{"pmid":"35996163","id":"PMC_35996163","title":"Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence.","date":"2022","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/35996163","citation_count":12,"is_preprint":false},{"pmid":"22187156","id":"PMC_22187156","title":"Native gel electrophoresis of human telomerase distinguishes active complexes with or without dyskerin.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/22187156","citation_count":12,"is_preprint":false},{"pmid":"23726835","id":"PMC_23726835","title":"Slow growth and unstable ribosomal RNA lacking pseudouridine in mouse embryonic fibroblast cells expressing catalytically inactive dyskerin.","date":"2013","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23726835","citation_count":12,"is_preprint":false},{"pmid":"32166868","id":"PMC_32166868","title":"Successful liver transplantation in short telomere syndromes without bone marrow failure due to DKC1 mutation.","date":"2020","source":"Pediatric transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/32166868","citation_count":12,"is_preprint":false},{"pmid":"26571381","id":"PMC_26571381","title":"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.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26571381","citation_count":11,"is_preprint":false},{"pmid":"18205399","id":"PMC_18205399","title":"Determination of protein-RNA interaction sites in the Cbf5-H/ACA guide RNA complex by mass spectrometric protein footprinting.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18205399","citation_count":11,"is_preprint":false},{"pmid":"32452087","id":"PMC_32452087","title":"CD8+ T-cell senescence and skewed lymphocyte subsets in young Dyskeratosis Congenita patients with PARN and DKC1 mutations.","date":"2020","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/32452087","citation_count":11,"is_preprint":false},{"pmid":"28337032","id":"PMC_28337032","title":"Drosophila dyskerin is required for somatic stem cell homeostasis.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28337032","citation_count":10,"is_preprint":false},{"pmid":"24303026","id":"PMC_24303026","title":"Dyskerin localizes to the mitotic apparatus and is required for orderly mitosis in human cells.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24303026","citation_count":10,"is_preprint":false},{"pmid":"30132373","id":"PMC_30132373","title":"Discovery of new chromen-4-one derivatives as telomerase inhibitors through regulating expression of dyskerin.","date":"2018","source":"Journal of enzyme inhibition and medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30132373","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46473,"output_tokens":8784,"usd":0.13559,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18751,"output_tokens":6310,"usd":0.125752,"stage2_stop_reason":"end_turn"},"total_usd":0.261342,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"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.\",\n      \"method\": \"Coimmunoprecipitation, immunofluorescence, immunogold electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP combined with two independent imaging methods (IF and immunogold EM) in a dedicated mechanistic study\",\n      \"pmids\": [\"7798307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro mutagenesis, in vivo pseudouridylation assay, growth phenotype analysis, snoRNA co-association assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis with functional pseudouridylation readout and snoRNA binding assay, multiple mutants tested\",\n      \"pmids\": [\"10523634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"EGFP fusion live-cell imaging, deletion/mutation analysis of NLS constructs, time-course expression in mammalian cell lines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-cell imaging with systematic deletion mapping of NLS elements, multiple mutant constructs tested\",\n      \"pmids\": [\"10556300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Epitope-tagged transfection, immunofluorescence, deletion analysis, co-IP (negative result for FANCA interaction)\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, deletion mapping of NLS, but limited to single method per claim\",\n      \"pmids\": [\"10744426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Murine embryonic stem cell knock-in, TRAP telomerase assay, real-time PCR for snoRNAs and TERC, pseudouridylation assays, telomere length measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (knock-in mutant ES cells, TRAP, pseudouridylation, telomere length) in a single rigorous study\",\n      \"pmids\": [\"15240872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, mutagenesis, cross-species assembly assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 1.95 Å with mutagenesis validation and cross-species functional assembly\",\n      \"pmids\": [\"16286935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, structural modeling of full RNP complex with guide and substrate RNAs, mapping of DC mutations\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — 2.1 Å crystal structure with full RNP modeling and disease mutation mapping\",\n      \"pmids\": [\"16427014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Conditionally active c-MYC transgene system, chromatin immunoprecipitation (ChIP), RT-PCR, cycloheximide treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus conditional transgene with protein synthesis inhibition, single lab, two orthogonal methods\",\n      \"pmids\": [\"17822678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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).\",\n      \"method\": \"Mouse knock-in model, X-inactivation pattern analysis (genetic epistasis), DNA damage foci immunofluorescence (co-localization with telomeres), etoposide treatment assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (telomerase dependence) combined with cellular imaging and DNA damage assays in a rigorous mouse model\",\n      \"pmids\": [\"18626023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Cre/loxP conditional knockout in mouse liver, Northern blot for rRNA precursors, immunofluorescence for fibrillarin, TUNEL apoptosis assay, CCl4 regeneration model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean tissue-specific KO with multiple orthogonal readouts (rRNA processing, nucleolar morphology, apoptosis, proliferation)\",\n      \"pmids\": [\"19917719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Single-molecule two-color coincidence detection (TCCD), systematic hTR subdomain deletions, recombinant dyskerin\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biophysical demonstration of protein-RNA interaction with mutagenesis mapping, single lab but rigorous method\",\n      \"pmids\": [\"19835419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Bioluminescent p27 IRES reporter mouse model, in vivo imaging, 48S preinitiation complex assembly assay, somatic mutation functional characterization\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including in vivo reporter, preinitiation complex assembly assay, and human tumor mutation functional validation\",\n      \"pmids\": [\"20587522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, polysome profiling, IRES reporter assay, p53 target gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple readouts (polysome, IRES reporter, p53 targets), single lab\",\n      \"pmids\": [\"20501855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, yeast genetics (point mutations disrupting Cbf5-Shq1 interaction), binding competition assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with genetic and biochemical validation of chaperone function\",\n      \"pmids\": [\"22117216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown of decay factors, TRAP telomerase assay, hTR localization imaging, RNA decay analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway placement by genetic rescue experiments with multiple decay pathway components, replicated across dyskerin- and PARN-deficient contexts\",\n      \"pmids\": [\"26950371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, colocalization imaging, RNA immunoprecipitation, siRNA depletion, mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, colocalization, RIP, and functional depletion studies with multiple orthogonal methods\",\n      \"pmids\": [\"23246433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro pseudouridylation kinetics assay with purified components (Cbf5, Nop10, Gar1), kcat/Km determination\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro enzymatic assay with kinetic parameters, single lab\",\n      \"pmids\": [\"22993689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"SUMO modification assay, telomerase activity (TRAP), telomere length measurement, stability assays with DC mutants\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM identification with functional consequences on telomerase RNA and telomere maintenance, single lab\",\n      \"pmids\": [\"23660516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Coimmunoprecipitation, H/ACA pre-RNP assembly assays with specific sno/scaRNAs and hTR H/ACA domain\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and assembly assays with multiple H/ACA RNAs and mutants, single lab\",\n      \"pmids\": [\"20008900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence (cell cycle-staged), siRNA knockdown, live cell imaging, spindle assembly checkpoint markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization imaging across cell cycle stages plus loss-of-function with multiple mitotic phenotype readouts, single lab\",\n      \"pmids\": [\"24303026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, ribosome purification, cell-free translation assay (reticulocyte system), mass spectrometry of ribosomal proteins, pseudouridylation level analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified ribosomes reconstituted in cell-free system, mass spectrometry, and pseudouridylation analysis provide mechanistic link\",\n      \"pmids\": [\"25934701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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).\",\n      \"method\": \"siRNA knockdown, bicistronic IRES reporter assays, ELISA for VEGF protein, RT-PCR for VEGF mRNA\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IRES reporter assay with protein/mRNA quantification, single lab, two orthogonal methods\",\n      \"pmids\": [\"23821664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Knock-in of catalytically inactive D125A mutant in MEFs, rRNA pseudouridylation assay, rRNA stability measurement\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — catalytic dead knock-in with direct rRNA pseudouridylation and stability measurements, single lab\",\n      \"pmids\": [\"23726835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical purification from in vitro transcription system, ChIP-seq, siRNA depletion, iPSC reprogramming efficiency assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — purification from defined in vitro system combined with ChIP-seq and functional depletion, multiple orthogonal methods\",\n      \"pmids\": [\"25407680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, siRNA knockdown of SMN and coilin, association assays with telomerase components\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and KD with multiple telomerase components, single lab\",\n      \"pmids\": [\"27215323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Pulldown assays with recombinant proteins, patient exome sequencing\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pulldown with recombinant proteins, single lab, single method\",\n      \"pmids\": [\"29178645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of dyskerin with hTR, rescue assays in dyskerin-deficient cells, TRAP telomerase assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping by mutation with multiple functional assays (binding, rescue of RNA accumulation, telomerase activity), single lab with orthogonal methods\",\n      \"pmids\": [\"30931479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, siRNA knockdown, telomerase activity assay, telomere length measurement\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus KD with telomere functional readout, single lab\",\n      \"pmids\": [\"31413099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), in vitro and in vivo functional assays, siRNA knockdown, overexpression\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus gain/loss-of-function with angiogenesis readout, single lab\",\n      \"pmids\": [\"31857720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Structural analysis, interaction assays (dyskerin-NOP10), rRNA pseudouridylation quantification in patient cells, zebrafish loss-of-function model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (structural mapping, interaction assay, patient rRNA analysis, zebrafish model) across two pedigrees\",\n      \"pmids\": [\"32554502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide RNAi screen, RIP-seq, RNA decay assays, catalytic mutant (D125A) overexpression, proteomics, xenograft mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RIP-seq plus RNA decay plus genetic rescue with catalytic mutant plus proteomics pathway analysis, multiple orthogonal methods\",\n      \"pmids\": [\"34026451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SUMO fusion constructs, subcellular fractionation, coimmunoprecipitation, telomerase RNA interaction assays, live-cell imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — SUMO fusion rescue, Co-IP, localization imaging, and telomerase RNA binding assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"33526451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq, pseudouridine sequencing, co-IP with RNA Pol II, siRNA knockdown, de novo protein synthesis assay (SUnSET), polysome profiling, patient cells analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — transcriptome-wide pseudouridine mapping combined with co-IP, de novo protein synthesis and polysome profiling, replicated in patient cells\",\n      \"pmids\": [\"37506213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, SUMO modification assays, CRISPR/Cas9 knock-in, xenograft mouse model, in vitro invasion assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, SUMO modification mapping, CRISPR knock-in, and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"37188742\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Dyskerin (DKC1) is the catalytic pseudouridine synthase subunit of H/ACA small nucleolar ribonucleoprotein (snoRNP) complexes, which it forms with NOP10, NHP2 (Nhp2), and GAR1 under the chaperone guidance of SHQ1; it converts specific uridines to pseudouridines in rRNA, snRNA, and mRNAs (the last in a guide RNA-independent, cotranscriptional manner that suppresses translation), and these pseudouridylation activities require an intact catalytic aspartate (D95 in yeast Cbf5; D125 in mouse). Dyskerin is also an obligate component of the human telomerase holoenzyme, binding directly to the H/ACA motif of hTR through its PUA domain and N-terminal residues to prevent oligoadenylation and EXOSC10/DCP2-XRN1-mediated degradation of hTR; SUMOylation at C-terminal lysine residues (especially K467) regulates its nuclear and nucleolar localization, which is essential for both its H/ACA RNP and telomerase functions. DKC1 is a direct transcriptional target of c-MYC and GATA1, and the DKC1 RNP complex can also act as an OCT4/SOX2 coactivator at enhancers of pluripotency genes; loss of dyskerin function reduces IRES-mediated translation of tumor suppressors (p27, p53) while paradoxically increasing IRES-mediated translation of VEGF, and selectively stabilizes mRNAs of ribosomal proteins that in turn suppress RAS/RAF/MEK/ERK signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1, #4, #29]. 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 [#1, #22]; 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 [#5, #6, #16]. 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 [#13, #25]. 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 [#9, #20, #22]. In a guide-independent, cotranscriptional mode, dyskerin associates with RNA polymerase II and pseudouridylates thousands of mRNAs to suppress their translation [#32]. 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 [#10, #14, #26]. 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 [#2, #31]. 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 [#7, #23, #27, #30]. Pathogenic DKC1 mutations cause dyskeratosis congenita, acting at the dyskerin–NOP10 and hTR-binding interfaces to reduce pseudouridylation and telomerase activity [#29, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal co-IP with immunofluorescence and immunogold EM in mammalian cells\",\n      \"pmids\": [\"7798307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define an enzymatic activity\", \"Functional consequence of the Nopp140 association unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified dyskerin as the pseudouridine synthase of H/ACA snoRNPs and pinpointed the catalytic aspartate, defining its core enzymatic function.\",\n      \"evidence\": \"Active-site mutagenesis (D95A) with in vivo rRNA pseudouridylation and snoRNA association assays in yeast Cbf5p\",\n      \"pmids\": [\"10523634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address telomerase role\", \"Mechanism of guide RNA selection not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped the determinants of dyskerin's nuclear/nucleolar trafficking, establishing where the enzyme must concentrate to act.\",\n      \"evidence\": \"EGFP live-cell imaging and deletion mapping of NLS/C-terminal lysine clusters in mammalian cells\",\n      \"pmids\": [\"10556300\", \"10744426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link localization to catalytic or telomerase output\", \"Regulation of trafficking unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated in a mammalian system that disease mutations partition dyskerin's two functions, separating effects on rRNA pseudouridylation from telomerase RNA stability.\",\n      \"evidence\": \"Knock-in mutant (A353V, G402E) mouse ES cells with TRAP, pseudouridylation, and telomere length assays\",\n      \"pmids\": [\"15240872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of mutation-specific effects not defined\", \"Did not resolve which defect drives disease\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided the structural logic for catalysis by showing Nop10 buttresses the Cbf5 active site and extends the RNA-binding cleft.\",\n      \"evidence\": \"1.95-Å crystal structure of archaeal Cbf5-Nop10 with mutagenesis and cross-species assembly\",\n      \"pmids\": [\"16286935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full RNP with guide and substrate not yet captured\", \"Human dyskerin structure inferred from archaeal ortholog\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended the structural model to the Cbf5-Nop10-Gar1 complex, explaining cofactor essentiality and locating the dyskeratosis congenita mutation cluster on the PUA domain.\",\n      \"evidence\": \"2.1-Å crystal structure with full RNP modeling and DC mutation mapping\",\n      \"pmids\": [\"16427014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Telomerase-specific RNP architecture not addressed\", \"Catalytic kinetics of cofactors not quantified here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed DKC1 expression under direct oncogenic control by identifying it as a c-MYC transcriptional target, linking it to proliferative programs.\",\n      \"evidence\": \"Conditional c-MYC transgene with ChIP and cycloheximide treatment\",\n      \"pmids\": [\"17822678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Downstream functional consequence of MYC-driven DKC1 not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed pathogenic Dkc1 mutations trigger a telomere-localized DNA damage response independent of telomere shortening, refining the mechanism of disease pathology.\",\n      \"evidence\": \"Mouse knock-in with X-inactivation genetic epistasis and DNA damage foci imaging\",\n      \"pmids\": [\"18626023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of telomere-localized damage unresolved\", \"Relationship to pseudouridylation defect not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional liver knockout (rRNA Northern, fibrillarin IF, TUNEL) and single-molecule TCCD of dyskerin-hTR binding with subdomain deletions\",\n      \"pmids\": [\"19917719\", \"19835419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"hTR-binding determinants on dyskerin not fully mapped at residue level\", \"Did not resolve how hTR escapes degradation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"p27 IRES reporter mouse with 48S preinitiation assembly assay, human tumor mutation (S485G), and siRNA with polysome profiling/IRES reporters\",\n      \"pmids\": [\"20587522\", \"20501855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular basis of IRES selectivity unresolved\", \"p53 effect shown by siRNA in single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Crystal structure of Shq1-Cbf5-Nop10-Gar1 with yeast genetics and binding competition\",\n      \"pmids\": [\"22117216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hand-off mechanism from SHQ1 to H/ACA RNA not kinetically resolved\", \"Human SHQ1-dyskerin interface inferred\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the hTR decay pathway dyskerin protects against, placing PAPD5/EXOSC10/DCP2/XRN1 downstream of failed dyskerin binding.\",\n      \"evidence\": \"RNAi of decay factors with TRAP rescue, hTR localization, and decay analysis (PARN deadenylation)\",\n      \"pmids\": [\"26950371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise recognition step distinguishing protected vs degraded hTR not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected dyskerin to rRNA quality control via SMUG1 and quantified how Nop10/Gar1 accelerate catalysis, deepening the enzymatic and partner picture.\",\n      \"evidence\": \"Co-IP/RIP/colocalization with SMUG1 plus in vitro pseudouridylation kinetics with purified archaeal Cbf5-Nop10-Gar1\",\n      \"pmids\": [\"23246433\", \"22993689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional importance of SMUG1 partnership in disease unclear\", \"Kinetics measured on archaeal components and tRNA substrate\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"23726835\", \"20008900\", \"23660516\", \"24303026\", \"23821664\", \"25934701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of opposite IRES effects (VEGF up vs p27/p53 down) unresolved\", \"Mitotic and SUMO findings from single labs\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a transcriptional-coactivator function distinct from catalysis, showing the dyskerin RNP supports OCT4/SOX2 at pluripotency enhancers and reprogramming.\",\n      \"evidence\": \"Biochemical purification from in vitro transcription system, ChIP-seq, and iPSC reprogramming with siRNA depletion\",\n      \"pmids\": [\"25407680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How snoRNAs modulate the coactivator activity not mechanistically defined\", \"Whether catalysis is required unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified SMN and coilin as negative regulators of dyskerin-hTR association, adding a regulatory layer to telomerase RNP assembly.\",\n      \"evidence\": \"Co-IP and siRNA knockdown of SMN/coilin with telomerase component association assays\",\n      \"pmids\": [\"27215323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs indirect regulation not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP/rescue/TRAP with K39E/K43E mutants; GATA1 ChIP/reporter in erythroid cells; HIF-1α ChIP in colorectal cancer\",\n      \"pmids\": [\"30931479\", \"31413099\", \"31857720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Erythroid and cancer ChIP findings from single labs\", \"Whether DKC1 directly binds HIF-1α promoter vs acts via cofactor unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Structural mapping, dyskerin-NOP10 interaction assays, patient rRNA pseudouridine quantification, zebrafish dkc1 model\",\n      \"pmids\": [\"32554502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific consequences of ribosomal dysregulation not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a catalysis-dependent mRNA-stabilizing function for ribosomal-protein transcripts that suppresses RAS/RAF/MEK/ERK signaling, and refined the SUMO-localization axis.\",\n      \"evidence\": \"RIP-seq, RNA decay, D125A catalytic-mutant rescue, proteomics, xenografts; plus SUMO3-fusion localization and GAR1 SIM mapping\",\n      \"pmids\": [\"34026451\", \"33526451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which DKC1 selects/stabilizes specific ribosomal-protein mRNAs unresolved\", \"Link between mRNA stabilization and pseudouridylation catalysis not directly shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pseudouridine-seq, RNA Pol II co-IP, SUnSET/polysome profiling, patient cells; plus SENP3 co-IP, SUMO mapping, CRISPR knock-in, xenografts\",\n      \"pmids\": [\"37506213\", \"37188742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dyskerin selects mRNA target sites without guide RNA unresolved\", \"Physiological scope of translational suppression across cell types unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 4, 16, 20, 22, 29, 32]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10, 14, 26, 30, 32]},\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [1, 22, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [23, 28]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [11, 12, 20, 21, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 2, 9, 15, 31]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 31]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 9, 22, 32]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 19, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 12, 20, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 23, 27, 28]}\n    ],\n    \"complexes\": [\"H/ACA snoRNP\", \"telomerase holoenzyme\"],\n    \"partners\": [\"NOP10\", \"GAR1\", \"NHP2\", \"NAF1\", \"SHQ1\", \"hTR/TERC\", \"SMUG1\", \"Nopp140\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}