2020
Shelterin and the replisome: at the intersection of telomere repair and replication
Cicconi A, Chang S. Shelterin and the replisome: at the intersection of telomere repair and replication. Current Opinion In Genetics & Development 2020, 60: 77-84. PMID: 32171974, DOI: 10.1016/j.gde.2020.02.016.Peer-Reviewed Original Research
2019
WRN helicase is a synthetic lethal target in microsatellite unstable cancers
Chan EM, Shibue T, McFarland JM, Gaeta B, Ghandi M, Dumont N, Gonzalez A, McPartlan JS, Li T, Zhang Y, Bin Liu J, Lazaro JB, Gu P, Piett CG, Apffel A, Ali SO, Deasy R, Keskula P, Ng RWS, Roberts EA, Reznichenko E, Leung L, Alimova M, Schenone M, Islam M, Maruvka YE, Liu Y, Roper J, Raghavan S, Giannakis M, Tseng YY, Nagel ZD, D’Andrea A, Root DE, Boehm JS, Getz G, Chang S, Golub TR, Tsherniak A, Vazquez F, Bass AJ. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 2019, 568: 551-556. PMID: 30971823, PMCID: PMC6580861, DOI: 10.1038/s41586-019-1102-x.Peer-Reviewed Original ResearchConceptsSynthetic lethal targetLethal targetGenetic eventsDepletion of WRNCRISPR-Cas9-mediated knockoutDNA repair pathwaysDNA repair processesSynthetic lethal relationshipSynthetic lethal vulnerabilitiesDNA repair defectsDNA mismatch repairCell cycle arrestWRN helicaseHelicase activityPromising drug targetHomologous recombinationRepair pathwaysRNA interferenceDNA breaksSynthetic lethalityWRNLethal relationshipExonuclease activityRepair defectsMismatch repair
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
2010
The telomere protein tankyrase 1 regulates DNA damage responses at telomeres
Chang S. The telomere protein tankyrase 1 regulates DNA damage responses at telomeres. Aging 2010, 2: 639-642. PMID: 21076181, PMCID: PMC2993793, DOI: 10.18632/aging.100221.Peer-Reviewed Original Research
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
Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesis
Guo X, Deng Y, Lin Y, Cosme‐Blanco W, Chan S, He H, Yuan G, Brown EJ, Chang S. Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesis. The EMBO Journal 2007, 26: 4709-4719. PMID: 17948054, PMCID: PMC2080807, DOI: 10.1038/sj.emboj.7601893.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsCells, CulturedDNA DamageDNA-Binding ProteinsEmbryo, MammalianFibroblastsMiceNeoplasmsProtein Serine-Threonine KinasesRNA, MessengerShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2Tumor Suppressor ProteinsRole of telomeres and telomerase in genomic instability, senescence and cancer
Deng Y, Chang S. Role of telomeres and telomerase in genomic instability, senescence and cancer. Laboratory Investigation 2007, 87: 1071-1076. PMID: 17767195, DOI: 10.1038/labinvest.3700673.Peer-Reviewed Original ResearchConceptsHuman cancersAnti-telomerase therapyAttractive therapeutic targetClinical trialsTherapeutic targetDNA damage responseRole of telomeresAbsence of p53Progressive lossHuman carcinomasSuppress tumorigenesisCancerLinear chromosomesCellular senescenceDamage responseTelomeric repeatsDysfunctional telomeresGenomic instabilityTelomeric structureChromosomal instabilityTelomeresP53TelomeraseImportant mechanismFunction resultsWRN 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
Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway
Laud PR, Multani AS, Bailey SM, Wu L, Ma J, Kingsley C, Lebel M, Pathak S, DePinho RA, Chang S. Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes & Development 2005, 19: 2560-2570. PMID: 16264192, PMCID: PMC1276730, DOI: 10.1101/gad.1321305.Peer-Reviewed Original ResearchConceptsWerner syndromeSister chromatidsT-SCETelomere sister chromatid exchangeElevated recombination ratesActivation of ALTWRN functionAberrant recombinationGenomic instabilityALT pathwayChromosomal aberrationsChromosomal instabilityTelomeresPremature agingDysfunctional cellsTumor formationChromatidsSister chromatid exchangesPathwayChromatid exchangesRecombinationRecombination rateCellsWRNMutantsModeling 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 processTelomeresSenescenceTumorigenesisPathwayMechanismAgingCancerSyndromeEndogenous 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
2002
Telomerase extracurricular activities
Chang S, DePinho R. Telomerase extracurricular activities. Proceedings Of The National Academy Of Sciences Of The United States Of America 2002, 99: 12520-12522. PMID: 12271146, PMCID: PMC130491, DOI: 10.1073/pnas.212514699.Peer-Reviewed Original ResearchTelomere 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