2017
Probing the Telomere Damage Response
Rai R, Chang S. Probing the Telomere Damage Response. Methods In Molecular Biology 2017, 1587: 133-138. PMID: 28324505, DOI: 10.1007/978-1-4939-6892-3_13.Peer-Reviewed Original ResearchConceptsTelomere dysfunctionDNA damage response signalsDNA damage repair pathwaysTelomere damage responseΓ-H2AXDamage repair pathwaysCheckpoint sensorNbs1 complexReplicative attritionMre11-Rad50Shelterin componentsDamage responseTelomeric DNADysfunctional telomeresRepair pathwaysDownstream effectorsComplete deletionTelomeresDNAPathwayTRF2Chk2Chk1KinaseEffectors
2015
Monitoring the DNA Damage Response at Dysfunctional Telomeres
Rai R, Chang S. Monitoring the DNA Damage Response at Dysfunctional Telomeres. Methods In Molecular Biology 2015, 1343: 175-180. PMID: 26420717, DOI: 10.1007/978-1-4939-2963-4_14.Peer-Reviewed Original ResearchConceptsDysfunctional telomeresDNA damage sensorDNA damage responseDNA damage fociSitu hybridization approachEukaryotic chromosomesShelterin componentsDNA repeatsGenomic stabilityDDR proteinsDamage responseTelomeric DNADDR pathwaysDamage fociChromosomal endsTelomere dysfunctionDamage sensorTelomeresDNA damageHybridization approachCellular viabilityPathwayProper maintenanceChromosomesRepeats
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 inhibitionPot1a Prevents Telomere Dysfunction and ATM-Dependent Neuronal Loss
Lee Y, Brown EJ, Chang S, McKinnon PJ. Pot1a Prevents Telomere Dysfunction and ATM-Dependent Neuronal Loss. Journal Of Neuroscience 2014, 34: 7836-7844. PMID: 24899707, PMCID: PMC4044246, DOI: 10.1523/jneurosci.4245-13.2014.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornAtaxia Telangiectasia Mutated ProteinsBeta-GalactosidaseBrainCell CycleCell Cycle ProteinsCells, CulturedDNA DamageDNA-Binding ProteinsEmbryo, MammalianFemaleGene Expression RegulationMaleMiceMice, TransgenicNestinNeuronsShelterin ComplexTelomereTelomere-Binding Proteins
2013
p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses
Wang Y, Sharpless N, Chang S. p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses. Journal Of Clinical Investigation 2013, 123: 4489-4501. PMID: 24091330, PMCID: PMC3784543, DOI: 10.1172/jci69574.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsApoptosisAtaxia Telangiectasia Mutated ProteinsBone Marrow TransplantationCell ProliferationCells, CulturedCyclin-Dependent Kinase Inhibitor p16Cyclin-Dependent Kinase Inhibitor p21DNA DamageDNA RepairDNA-Binding ProteinsFemaleHematopoiesisHematopoietic Stem CellsIntestine, SmallMaleMiceMice, SCIDMice, TransgenicProtein StabilitySequence DeletionSpleenTelomereTelomere HomeostasisTumor Suppressor Protein p53ConceptsHematopoietic cellsDeletion of p21P21-dependent cell cycle arrestOrgan impairmentTelomere dysfunctionCell cycle arrestMouse modelDNA damage responseSmall intestineFunctional defectsCell functionProliferative capacityP53-dependent apoptosisCycle arrestDysfunctional telomeresCellular senescenceDysfunctionP53-dependent DNA damage responseProliferative cellsHematopoietic systemProtective functionTumor suppressorProliferative defectP53 stabilizationCellsFunctional 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 mutation
2011
Probing the Telomere Damage Response
Rai R, Chang S. Probing the Telomere Damage Response. Methods In Molecular Biology 2011, 735: 145-150. PMID: 21461819, PMCID: PMC3690558, DOI: 10.1007/978-1-61779-092-8_14.Peer-Reviewed Original ResearchConceptsTelomere dysfunctionDNA damage response signalsDNA damage repair pathwaysTelomere damage responseΓ-H2AXDamage repair pathwaysCheckpoint sensorNbs1 complexReplicative attritionMre11-Rad50Shelterin componentsDamage responseTelomeric DNADysfunctional telomeresRepair pathwaysDownstream effectorsComplete deletionTelomeresDNAPathwayTRF2Chk2Chk1KinaseEffectors
2009
Replicative Senescence as an Intrinsic Tumor-Suppressor Mechanism
Chang S. Replicative Senescence as an Intrinsic Tumor-Suppressor Mechanism. 2009, 201-217. DOI: 10.1007/978-1-4419-1075-2_8.Peer-Reviewed Original ResearchDysfunctional telomeresGenomic instabilityIntrinsic tumor suppressor mechanismsDNA damage response pathwayProtein-DNA complexesDamage response pathwayTumor suppressor mechanismEukaryotic chromosomal endsEnds of chromosomesP53-dependent senescenceAbsence of p53Complex cytogenetic profileTriggers senescenceDDR pathwaysResponse pathwaysChromosomal endsReplicative senescenceTelomere dysfunctionCellular senescenceOnset of cancerTelomeresSenescenceCancer progressionEpithelial tissuesHuman carcinomasGcn5 and SAGA Regulate Shelterin Protein Turnover and Telomere Maintenance
Atanassov BS, Evrard YA, Multani AS, Zhang Z, Tora L, Devys D, Chang S, Dent SY. Gcn5 and SAGA Regulate Shelterin Protein Turnover and Telomere Maintenance. Molecular Cell 2009, 35: 352-364. PMID: 19683498, PMCID: PMC2749492, DOI: 10.1016/j.molcel.2009.06.015.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedChromosome AberrationsDNA Breaks, Double-StrandedDNA RepairGene DeletionHumansMiceModels, BiologicalP300-CBP Transcription FactorsProteasome InhibitorsProtein StabilityShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 1Thiolester HydrolasesUbiquitin ThiolesteraseConceptsSAGA complexTelomeric shelterin complexDeletion of GCN5Accessibility of chromatinBona fide componentTRF1 levelsGene regulationShelterin complexTelomere maintenanceMammalian cellsTranscription factorsGCN5DNA repairFide componentRepair proteinsTelomere dysfunctionProtein turnoverHuman cellsUbiquitin-specific protease 22Biochemical studiesOverexpression of USP22USP22ComplexesTurnoverChromatin
2008
Telomere dysfunction and tumour suppression: the senescence connection
Deng Y, Chan SS, Chang S. Telomere dysfunction and tumour suppression: the senescence connection. Nature Reviews Cancer 2008, 8: 450-458. PMID: 18500246, PMCID: PMC3688269, DOI: 10.1038/nrc2393.Peer-Reviewed Original ResearchConceptsTelomere dysfunctionDysfunctional telomeresDNA damage responseKey PointsTelomeresEukaryotic chromosomesGenome instabilityShelterin complexApoptotic programDamage responseRepetitive sequencesCellular senescenceTelomeric endTumor suppressionProtein resultsP53 pathwayMutant p53TelomeresSpontaneous tumorigenesisSenescenceTumorigenesisMouse modelChromosomesDysfunctionProteinApoptosisDual roles of telomere dysfunction in initiation and suppression of tumorigenesis
Cosme-Blanco W, Chang S. Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis. Experimental Cell Research 2008, 314: 1973-1979. PMID: 18448098, PMCID: PMC3690559, DOI: 10.1016/j.yexcr.2008.03.011.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksDysfunctional telomeresGenomic instabilityPotent tumor suppressor mechanismTumorigenic potentialSimple repeat sequencesTumor suppressor mechanismDouble-strand breaksCell tumorigenic potentialSuppression of tumorigenesisCancer cellsChromosomal endsTelomere dysfunctionCellular senescenceRepeat sequencesGenetic changesTelomeresGenetic lesionsP53 pathwayTumor initiationDicentric chromosomesSuppressor mechanismIntact p53 pathwayHuman carcinomasRare cells
2007
Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescence
Cosme-Blanco W, Shen MF, Lazar AJ, Pathak S, Lozano G, Multani AS, Chang S. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescence. EMBO Reports 2007, 8: 497-503. PMID: 17396137, PMCID: PMC1866197, DOI: 10.1038/sj.embor.7400937.Peer-Reviewed Original ResearchConceptsP53-dependent cellular senescenceSpontaneous tumorigenesisCellular senescenceCellular senescence pathwaysSenescence pathwaysCell cycle arrestSkin carcinomasSenescence markersTumorigenesisMiceDysfunctional telomeresTumor suppressionTelomere dysfunctionP53ApoptosisVivoSuppressionCarcinomaDysfunctionPathwaySenescenceWRN 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
2005
Modeling aging and cancer in the telomerase knockout mouse
Chang S. Modeling aging and cancer in the telomerase knockout mouse. Mutation Research/Fundamental And Molecular Mechanisms Of Mutagenesis 2005, 576: 39-53. PMID: 15927211, DOI: 10.1016/j.mrfmmm.2004.08.020.Peer-Reviewed Original ResearchConceptsTelomere dysfunctionRole of telomeresTelomerase-null miceTelomerase knockout miceTelomerase-deficient miceOrganismal agingSomatic cellsMammalian organismsTight regulationCellular responsesTelomerase activityNull miceKnockout miceTelomeresMouse modelTelomeraseOrganismsMiceDeficient miceRegulationAgingCellsCancer
2004
A mouse model of Werner Syndrome: what can it tell us about aging and cancer?
Chang S. A mouse model of Werner Syndrome: what can it tell us about aging and cancer? The International Journal Of Biochemistry & Cell Biology 2004, 37: 991-999. PMID: 15743673, DOI: 10.1016/j.biocel.2004.11.007.Peer-Reviewed Original ResearchConceptsMolecular mechanismsWerner syndromePremature agingConsequent cellular responsesGene functionMammalian agingDysfunctional telomeresGenetic pathwaysReplicative senescenceTelomere dysfunctionCellular responsesGenetic platformProgeroid syndromesMolecular levelMouse modelRecent studiesAging processTelomeresSenescenceTumorigenesisPathwayMechanismAgingCancerSyndrome
2003
Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression
Chang S, Khoo C, Naylor M, Maser R, DePinho R. Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. Genes & Development 2003, 17: 88-100. PMID: 12514102, PMCID: PMC195968, DOI: 10.1101/gad.1029903.Peer-Reviewed Original ResearchConceptsInk4a/Lung metastasesSubcutaneous tumorsTumor progressionTelomerase activationSubcutaneous tumor formationAdvanced human cancersTail vein injectionTelomere dysfunctionLate passagesMalignant endpointsTelomerase-independent alternative lengtheningImmunocompromised miceFunctional differencesCytogenetic profileMetastatic activityDysfunctionMetastasisCancer cell genomeTumor formationChromosomal aberrationsHuman cancersMarked increaseInitiated cellsMouse embryonic fibroblast cultures
2002
Telomere dysfunction provokes regional amplification and deletion in cancer genomes
O'Hagan R, Chang S, Maser R, Mohan R, Artandi S, Chin L, DePinho R. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2002, 2: 149-155. PMID: 12204535, DOI: 10.1016/s1535-6108(02)00094-6.Peer-Reviewed Original ResearchConceptsTelomere dysfunctionAged humansMajor cancersPathogenic significanceDysfunctionEpithelial carcinogenesisArray comparative genomic hybridizationComparative genomic hybridizationCancer hotspotsGenomic profilesNonreciprocal translocationsTumorsMiceCarcinogenesisGenomic hybridizationChromosomal instability
2000
Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation
Wong K, Chang S, Weiler S, Ganesan S, Chaudhuri J, Zhu C, Artandi S, Rudolph K, Gottlieb G, Chin L, Alt F, DePinho R. Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nature Genetics 2000, 26: 85-88. PMID: 10973255, DOI: 10.1038/79232.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell NucleusCell SurvivalChromosome AberrationsChromosomesDNA FragmentationDNA RepairDose-Response Relationship, RadiationFibroblastsGenotypeIn Situ Nick-End LabelingKineticsMiceMice, TransgenicModels, GeneticRadiation ToleranceRadiation, IonizingTelomereThymus GlandTime FactorsConceptsMouse embryonic fibroblastsTelomere functionOrganismal responsesLinear eukaryotic chromosomesDNA repair machineryTelomerase RNA geneNon-homologous endImpairs DNA repairRole of telomeraseTelomerase-deficient miceEukaryotic chromosomesRNA genesYeast telomeresNucleoprotein complexesRepair machineryDNA repairIntact telomeresCrypt stem cellsEmbryonic fibroblastsTelomere dysfunctionDe novo synthesisChromosomal repairGenetic instabilityPrimary thymocytesRate of apoptosisTelomere 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 complexesInhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene Delivery
Rudolph K, Chang S, Millard M, Schreiber-Agus N, DePinho R. Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene Delivery. Science 2000, 287: 1253-1258. PMID: 10678830, DOI: 10.1126/science.287.5456.1253.Peer-Reviewed Original ResearchConceptsLiver cirrhosisChronic diseasesEnd-stage organ failureChronic liver injuryImproved liver functionExperimental liver cirrhosisLiver injuryOrgan failureLiver functionTelomerase-deficient miceTelomere dysfunctionHigh cellular turnoverTelomerase therapyChemical ablationCirrhosisAdenoviral deliveryLiver regenerationSuch diseasesDiseaseMiceTelomerase activityDysfunctionLiverCellular turnoverShort dysfunctional telomeres