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
2006
Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres
Wu L, Multani AS, He H, Cosme-Blanco W, Deng Y, Deng JM, Bachilo O, Pathak S, Tahara H, Bailey SM, Deng Y, Behringer RR, Chang S. Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres. Cell 2006, 126: 49-62. PMID: 16839876, DOI: 10.1016/j.cell.2006.05.037.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Cycle ProteinsCells, CulturedCellular SenescenceChromosome AberrationsDNA DamageDNA RepairDNA-Binding ProteinsGene SilencingGenes, cdcGenomic InstabilityMiceMice, KnockoutNuclear ProteinsProtein IsoformsRecombination, GeneticSequence HomologyShelterin ComplexSister Chromatid ExchangeTelomereTelomere-Binding ProteinsConceptsAberrant homologous recombinationHomologous recombinationTelomere sister chromatid exchangeDNA damage checkpoint activationOverall genomic stabilityTelomere length regulationDNA damage machineryDNA damage responseT-loop structureChromosomal end protectionMammalian telomeresPOT1 proteinsTelomere integrityCheckpoint activationGenomic stabilityLength regulationMouse genomeDamage responseEnd protectionReplicative senescenceDNA breaksRich overhangTelomeresChromosomal instabilityConditional deletion
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 rateCellsWRNMutantsTrp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005, 7: 469-483. PMID: 15894267, DOI: 10.1016/j.ccr.2005.04.023.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCadherinsCarcinoma, Pancreatic DuctalCentrosomeChromosomal InstabilityChromosome AberrationsCytogenetic AnalysisDisease ProgressionGene ExpressionGene Expression RegulationGene RearrangementGenes, Tumor SuppressorHomeodomain ProteinsIntegrasesMiceMice, Inbred C57BLMice, Inbred StrainsMice, Mutant StrainsMice, TransgenicMutation, MissenseNeoplasm MetastasisOncogene Proteins v-erbBProto-Oncogene Proteins p21(ras)Ras ProteinsSurvival AnalysisTelomereTrans-ActivatorsTranslocation, GeneticTumor Suppressor Protein p53ConceptsPancreatic ductal adenocarcinomaTumor suppressor gene pathwaysDistinct genetic pathwaysGenetic requirementsGenetic pathwaysGenomic instabilityGene pathwaysChromosomal instabilityEndogenous expressionHuman diseasesNonreciprocal translocationsDuctal adenocarcinomaMetastatic pancreatic ductal adenocarcinomaHuman carcinomasDisease pathogenesisMouse pancreasDifferent biological behaviorPathwayMetastatic carcinomaPrimary carcinomaTreatment strategiesCarcinomaBiological behaviorDevelopment of detectionTranslocation
2004
Essential role of limiting telomeres in the pathogenesis of Werner syndrome
Chang S, Multani AS, Cabrera NG, Naylor ML, Laud P, Lombard D, Pathak S, Guarente L, DePinho RA. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nature Genetics 2004, 36: 877-882. PMID: 15235603, DOI: 10.1038/ng1389.Peer-Reviewed Original ResearchConceptsWerner syndromeCultured cellsComplex cellular phenotypesElevated genomic instabilityDNA damage fociPremature aging syndromesWRN deficiencyReplicative senescenceCellular phenotypesGenomic instabilityAging syndromesGenetic dataMutational inactivationPremature senescenceChromosomal instabilityTelomerase expressionHair grayingPremature agingDisease phenotypeEssential roleWRNMice nullSenescenceAutosomal recessive diseaseType II diabetes
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
2001
Modeling chromosomal instability and epithelial carcinogenesis in the telomerase-deficient mouse
Chang S, Khoo C, DePinho R. Modeling chromosomal instability and epithelial carcinogenesis in the telomerase-deficient mouse. Seminars In Cancer Biology 2001, 11: 227-238. PMID: 11407947, DOI: 10.1006/scbi.2000.0374.Peer-Reviewed Original ResearchConceptsComplex cytogenetic profileHuman carcinomasChromosomal structural aberrationsTelomerase-deficient miceEukaryotic chromosomesNucleoprotein complexesGenomic instabilitySpecies distinctionP53 mutant miceChromosomal instabilityTumor suppressor gene mutationsShort telomeresSuppressor gene mutationsMutant miceStructural aberrationsEpithelial carcinogenesisGene mutationsCytogenetic profileChromosomesTelomeresMiceMutationsRegulationHumansAneuploidy