2020
Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly
Cicconi A, Rai R, Xiong X, Broton C, Al-Hiyasat A, Hu C, Dong S, Sun W, Garbarino J, Bindra RS, Schildkraut C, Chen Y, Chang S. Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly. Nature Communications 2020, 11: 5861. PMID: 33203878, PMCID: PMC7672075, DOI: 10.1038/s41467-020-19674-0.Peer-Reviewed Original ResearchAminopeptidasesAnimalsBinding SitesCalorimetryCell Cycle ProteinsCytoskeletal ProteinsDipeptidyl-Peptidases and Tripeptidyl-PeptidasesDNA DamageFibroblastsHeLa CellsHistonesHumansMiceMicrocephalyMutationProtein Interaction Domains and MotifsSerine ProteasesShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2
2017
Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer
Chen C, Gu P, Wu J, Chen X, Niu S, Sun H, Wu L, Li N, Peng J, Shi S, Fan C, Huang M, Wong CC, Gong Q, Kumar-Sinha C, Zhang R, Pusztai L, Rai R, Chang S, Lei M. Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nature Communications 2017, 8: 14929. PMID: 28393832, PMCID: PMC5394241, DOI: 10.1038/ncomms14929.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsConserved SequenceDNA DamageDNA Mutational AnalysisDNA RepairGenomic InstabilityHumansMiceModels, MolecularMolecular ChaperonesMutationNeoplasmsPhosphoproteinsProstaglandin-E SynthasesProtein BindingProtein Structure, SecondaryScattering, Small AngleShelterin ComplexStructure-Activity RelationshipTelomere-Binding ProteinsX-Ray DiffractionConceptsTelomerase-mediated telomere extensionHuman cancersDNA damage responseC-terminal mutationsOB foldsHuman POT1Chromosome endsGenome instabilityPOT1-TPP1Telomere extensionDamage responseStable heterodimerA-NHEJStructural insightsC-terminusInappropriate repairTPP1POT1Heart-shaped structureMissense mutationsTerminal portionMutationsDomainMutantsTelomeres
2016
Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis
Gu P, Wang Y, Bisht KK, Wu L, Kukova L, Smith EM, Xiao Y, Bailey SM, Lei M, Nandakumar J, Chang S. Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis. Oncogene 2016, 36: 1939-1951. PMID: 27869160, PMCID: PMC5383532, DOI: 10.1038/onc.2016.405.Peer-Reviewed Original ResearchConceptsComplex cytogenetic rearrangementsHuman cancersInvasive breast carcinomaAberrant DNA damageMouse mammary epitheliumBreast carcinomaMammary epitheliumHematopoietic malignanciesConditional deletionAlternative non-homologous endChromosomal aberrationsCancer initiationRepair responseFamilial mutationsOncogenic mutationsCytogenetic rearrangementsTumorigenesisCancerDNA damageMutationsGenetic changesCarcinomaDNA damage responseMalignancy
2014
Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A
Gupta R, Dong Y, Solomon PD, Wettersten HI, Cheng CJ, Min JN, Henson J, Dogra SK, Hwang SH, Hammock BD, Zhu LJ, Reddel RR, Saltzman WM, Weiss RH, Chang S, Green MR, Wajapeyee N. Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: e3062-e3071. PMID: 25024194, PMCID: PMC4121806, DOI: 10.1073/pnas.1411370111.Peer-Reviewed Original ResearchConceptsP53-mediated transcriptional activationCyclin-dependent kinase inhibitor 1AMutant p53Telomerase inhibitionTumor suppressor p53Transcriptional activationSynergistic tumor suppressionTelomere dysfunctionCheckpoint proteinsP53 upregulated modulatorTumor suppressionCDK inhibitorsSuppressor p53Inhibitor 1AP53 activityTelomeraseHuman cancersCancer cell linesApoptosis inductionPharmacological inhibitionApoptosisCell linesPharmacological restorationP21Growth inhibition
2013
Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus
Gu P, Chang S. Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus. Aging Cell 2013, 12: 1100-1109. PMID: 23869908, PMCID: PMC4083614, DOI: 10.1111/acel.12139.Peer-Reviewed Original ResearchConceptsCTC1 mutationsFrameshift mutantsTelomere dysfunctionUnstable protein productsDNA/protein structuresFirst biochemical characterizationDNA PolαStn1-Ten1CST complexFused chromosomeGenome stabilityTelomere functionTelomere replicationMissense mutantsCTC1-STN1Functional characterizationBiochemical characterizationProtein productsProtein structureRare recessive disorderTelomeresMutantsMissense mutationsNovel mechanismFrameshift mutationThe mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability
Min JN, Tian Y, Xiao Y, Wu L, Li L, Chang S. The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability. Cell Research 2013, 23: 1396-1413. PMID: 23979016, PMCID: PMC3847565, DOI: 10.1038/cr.2013.113.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsCells, CulturedCellular SenescenceChromatinChromatin Assembly and DisassemblyDNA Breaks, Double-StrandedDNA HelicasesDNA RepairDNA ReplicationFibroblastsGenomic InstabilityHydroxyureaMiceMice, Inbred C57BLMice, KnockoutMutationNucleic Acid Synthesis InhibitorsTelomereTumor Suppressor Protein p53ConceptsHomology-directed DNA repairEfficient telomere replicationGenome stabilityTelomere replicationDependent DNA damage responseDNA double-strand breaksDNA damage responseDNA damage fociMammalian cell linesATPase catalytic subunitConditional knockout approachDouble-strand breaksINO80 chromatinChromatin remodelingOrganismal functionTranscriptional regulationFragile telomeresDamage responseDNA replicationCatalytic subunitDamage fociDysfunctional telomeresSingle-strand DNADNA repairKnockout approachCancer chromosomes going to POT1
Chang S. Cancer chromosomes going to POT1. Nature Genetics 2013, 45: 473-475. PMID: 23619786, PMCID: PMC4040961, DOI: 10.1038/ng.2617.Peer-Reviewed Original Research
2011
A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms
Chen Y, Rai R, Zhou ZR, Kanoh J, Ribeyre C, Yang Y, Zheng H, Damay P, Wang F, Tsujii H, Hiraoka Y, Shore D, Hu HY, Chang S, Lei M. A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms. Nature Structural & Molecular Biology 2011, 18: 213-221. PMID: 21217703, PMCID: PMC3688267, DOI: 10.1038/nsmb.1974.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAmino Acid SequenceAnimalsCells, CulturedCrystallography, X-RayFungal ProteinsHeLa CellsHumansModels, MolecularMolecular Sequence DataMutationNuclear Magnetic Resonance, BiomolecularProtein BindingProtein Interaction Domains and MotifsSaccharomycetalesSchizosaccharomycesShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2ConceptsRap1 C-terminusDifferent interacting partnersProtein Rap1Fission yeastTelomere protectionInteracting partnerTranscriptional silencingDifferent organismsC-terminusFunctional analysisInteraction moduleYeastRap1Different functionsOrganismsTaz1Sir3TRF2MammalianTelomeresSilencingMammalsMotifCrystal structureRegulation
2008
Evidence that senescent human prostate epithelial cells enhance tumorigenicity: Cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT
Bhatia B, Multani AS, Patrawala L, Chen X, Calhoun‐Davis T, Zhou J, Schroeder L, Schneider‐Broussard R, Shen J, Pathak S, Chang S, Tang DG. Evidence that senescent human prostate epithelial cells enhance tumorigenicity: Cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT. International Journal Of Cancer 2008, 122: 1483-1495. PMID: 18059027, DOI: 10.1002/ijc.23222.Peer-Reviewed Original ResearchConceptsHuman prostate epithelial cellsNHP cellsProstate epithelial cellsCell fusionVivo tumorigenicityTumor cellsTumor developmentNormal human prostate epithelial cellsEpithelial cellsAR mRNA expressionCell-cell fusionProstate cancer cell linesPotential mechanismsGene expression analysisP16INK4a protein expressionModel cell systemGenomic stabilityLNCaP prostate cancerCancer cell linesExogenous p16Expression analysisProstate cancerSenescent fibroblastsProgenitor markersProstate tumorigenesis
2007
Overexpression of the Low Molecular Weight Cyclin E in Transgenic Mice Induces Metastatic Mammary Carcinomas through the Disruption of the ARF-p53 Pathway
Akli S, Van Pelt CS, Bui T, Multani AS, Chang S, Johnson D, Tucker S, Keyomarsi K. Overexpression of the Low Molecular Weight Cyclin E in Transgenic Mice Induces Metastatic Mammary Carcinomas through the Disruption of the ARF-p53 Pathway. Cancer Research 2007, 67: 7212-7222. PMID: 17671189, DOI: 10.1158/0008-5472.can-07-0599.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAnimalsApoptosisBlotting, WesternCyclin ECyclin-Dependent Kinase Inhibitor p16FemaleGene Expression Regulation, NeoplasticGene SilencingHumansImmunoenzyme TechniquesIn Situ Nick-End LabelingLoss of HeterozygosityLung NeoplasmsMammary Neoplasms, ExperimentalMiceMice, KnockoutMice, TransgenicMutationPolymerase Chain ReactionTumor Cells, CulturedTumor Suppressor Protein p53ConceptsFull-length cyclin ECyclin E overexpressionCyclin EARF-p53 pathwayTransgenic miceLow molecular weight cyclin EE overexpressionMetastatic mammary carcinomaMammary tumor formationWeight cyclin ETumor-bearing animalsBreast cancer tumorigenesisBreast cancer cellsMouse mammary tumor virus promoterLow molecular weight isoformsLMW formsOncologic roleInactivation of p53Mammary carcinomaBreast cancerMammary adenocarcinomaLoss of heterozygosityCancer tumorigenesisMammary epithelial cellsMolecular weight isoformsWRN at telomeres: implications for aging and cancer
Multani AS, Chang S. WRN at telomeres: implications for aging and cancer. Journal Of Cell Science 2007, 120: 713-721. PMID: 17314245, DOI: 10.1242/jcs.03397.Peer-Reviewed Original ResearchConceptsWerner syndromeHuman Werner syndromePremature aging syndromesRecent genetic evidenceAge-related pathologiesGenome stabilityWRN deficiencyTelomere maintenanceDNA replicationGenetic evidenceSingle gene defectsTelomere dysfunctionCellular senescenceAging syndromesMolecular levelPremature agingEarly cancer onsetWRNGene defectsCancer onsetMajor roleTelomeresSenescenceRapid onsetProtein
2006
POT1b protects telomeres from end‐to‐end chromosomal fusions and aberrant homologous recombination
He H, Multani AS, Cosme‐Blanco W, Tahara H, Ma J, Pathak S, Deng Y, Chang S. POT1b protects telomeres from end‐to‐end chromosomal fusions and aberrant homologous recombination. The EMBO Journal 2006, 25: 5180-5190. PMID: 17053789, PMCID: PMC1630418, DOI: 10.1038/sj.emboj.7601294.Peer-Reviewed Original Research
2005
Modeling premature aging syndromes with the telomerase knockout mouse.
Chang S. Modeling premature aging syndromes with the telomerase knockout mouse. 2005, 5: 153-8. PMID: 15974868, DOI: 10.2174/1566524053586662.Peer-Reviewed Original ResearchMeSH KeywordsAging, PrematureAnimalsDisease Models, AnimalMiceMice, KnockoutMutationSyndromeTelomeraseConceptsTelomerase knockout miceMammalian agingGenomic instabilityDNA damage pathwayPremature aging syndromesCellular declineMolecular basisAging syndromesAging processDamage pathwayKnockout miceMolecular pathwaysShort telomeresHuman agingPrimate model systemMouse modelModel systemBiological mechanismsPhenotypePhysiological changesPathwayUnprecedented opportunityDeleterious effectsTelomeresMice
2004
Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects
Tuveson D, Shaw A, Willis N, Silver D, Jackson E, Chang S, Mercer K, Grochow R, Hock H, Crowley D, Hingorani S, Zaks T, King C, Jacobetz M, Wang L, Bronson R, Orkin S, DePinho R, Jacks T. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 2004, 5: 375-387. PMID: 15093544, DOI: 10.1016/s1535-6108(04)00085-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell CycleCell DivisionCell Transformation, NeoplasticCellular SenescenceCongenital AbnormalitiesCrosses, GeneticCyclin-Dependent Kinase Inhibitor p16Embryo, MammalianFemaleFibroblastsGene Expression Regulation, DevelopmentalGenes, rasIntegrasesMaleMiceMice, Inbred C57BLMice, TransgenicMutationNeoplasmsStem CellsTumor Suppressor Protein p14ARFTumor Suppressor Protein p53Viral ProteinsConceptsCanonical Ras effectorRas effectorsOncogenic RasEmbryonic developmentAbnormal cellular proliferationDevelopmental defectsRas oncogeneGenetic lesionsConditional expressionWidespread expressionK-RasG12DCellular proliferationFurther genetic abnormalitiesEnhanced proliferationOncogeneProliferationExpressionGenetic abnormalitiesEffectorsMutationsAllelesRegulationPathwayFibroblastsFrank malignancy
2000
Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice
Artandi S, Chang S, Lee S, Alson S, Gottlieb G, Chin L, DePinho R. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 2000, 406: 641-645. PMID: 10949306, DOI: 10.1038/35020592.Peer-Reviewed Original ResearchConceptsEpithelial cancersSoft tissue sarcomasTelomere lengthP53 mutant miceTumor suppressor gene mutationsSuppressor gene mutationsNon-reciprocal translocationsTissue sarcomasTelomere dysfunctionAged humansMutant miceCytogenetic featuresCancerMiceHuman carcinomasGene mutationsEpithelial renewalTelomerase expressionCritical reductionCarcinomaDysfunctionHigh rateReverse transcriptaseEukaryotic chromosomesNucleoprotein complexes