2023
Pot1b −/− tumors activate G-quadruplex-induced DNA damage to promote telomere hyper-elongation
Takasugi T, Gu P, Liang F, Staco I, Chang S. Pot1b −/− tumors activate G-quadruplex-induced DNA damage to promote telomere hyper-elongation. Nucleic Acids Research 2023, 51: 9227-9247. PMID: 37560909, PMCID: PMC10516629, DOI: 10.1093/nar/gkad648.Peer-Reviewed Original ResearchConceptsDNA damage responseDamage responseReplication protein A (RPA) complexDependent DNA damage responseTelomere length homeostasisTelomere maintenance mechanismLength homeostasisTelomerase recruitmentPOT1 proteinsHuman POT1Mouse genomeLength maintenanceFunction disruptsReplicative immortalityTelomeresPOT1 mutationsDNA damageHuman cancersLonger telomeresPOT1bMaintenance mechanismsSerial transplantationA complexesSimilar mechanismMutations
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
2010
Aurora Kinase A Promotes Ovarian Tumorigenesis through Dysregulation of the Cell Cycle and Suppression of BRCA2
Yang G, Chang B, Yang F, Guo X, Cai K, Xiao X, Wang H, Sen S, Hung M, Mills G, Chang S, Multani A, Mercado-Uribe I, Liu J. Aurora Kinase A Promotes Ovarian Tumorigenesis through Dysregulation of the Cell Cycle and Suppression of BRCA2. Clinical Cancer Research 2010, 16: 3171-3181. PMID: 20423983, PMCID: PMC2930838, DOI: 10.1158/1078-0432.ccr-09-3171.Peer-Reviewed Original ResearchConceptsDNA damage responseGenomic instabilitySmall hairpin RNADamage responseExpression ratioCell cycle progressionOvarian cancer cell line SKOV3Multiple human cancersColon cancer samplesKnockdown of AuroraCell cycle alterationsMitotic spindleCell cycle dysregulationCell line SKOV3Cycle progressionExpression of AuroraMolecular mechanismsCell cycleAurora kinasesHairpin RNATumor growthCentrosome amplificationHuman cancersHuman ovarian cancerHigh-grade ovarian serous carcinoma
2007
Role 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 results
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