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
2021
Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres
Gu P, Jia S, Takasugi T, Tesmer VM, Nandakumar J, Chen Y, Chang S. Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres. Nature Communications 2021, 12: 5514. PMID: 34535663, PMCID: PMC8448735, DOI: 10.1038/s41467-021-25799-7.Peer-Reviewed Original ResearchConceptsDNA damage responseTelomerase recruitmentPOT1 proteinsDamage responseATR-dependent DNA damage responseNon-homologous end-joining DNA repair pathwayRecruitment of telomeraseC-strand fillAmino acidsDNA repair pathwaysUnique amino acidsTEN1 (CST) complexTelomere extensionCTC1-STN1Stable heterodimerRepair pathwaysC-terminusDistinct functionsPOT1bPOT1aTelomeresC-strandG-strandTPP1Protein
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
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
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 stabilizationCellsThe 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 approachSingle strand DNA binding proteins 1 and 2 protect newly replicated telomeres
Gu P, Deng W, Lei M, Chang S. Single strand DNA binding proteins 1 and 2 protect newly replicated telomeres. Cell Research 2013, 23: 705-719. PMID: 23459151, PMCID: PMC3641597, DOI: 10.1038/cr.2013.31.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsCell LineChromatidsDNA DamageDNA RepairDNA, Single-StrandedDNA-Binding ProteinsGenomic InstabilityHumansMiceMice, KnockoutMitochondrial ProteinsProtein BindingRadiation, IonizingRNA InterferenceRNA, Small InterferingShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2ConceptsGenome stabilitySingle-strand DNAHeterotrimeric protein complexDNA damage responseTelomere end protectionProtein 1Subset of telomeresTelomeric ssDNAProtein complexesTelomeric DNADamage responseG-overhangsEnd protectionConditional knockout miceTelomeresΔ miceDNAPOT1aDevelopmental abnormalitiesStrand DNACritical roleKnockout miceINTS3F allelePOT1b
2012
Chromosome ends teach unexpected lessons on DNA damage signalling
Chang S. Chromosome ends teach unexpected lessons on DNA damage signalling. The EMBO Journal 2012, 31: 3380-3381. PMID: 22842787, PMCID: PMC3419931, DOI: 10.1038/emboj.2012.199.Peer-Reviewed Original Research
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 ResearchDefending the end zone: Studying the players involved in protecting chromosome ends
Chan SS, Chang S. Defending the end zone: Studying the players involved in protecting chromosome ends. FEBS Letters 2010, 584: 3773-3778. PMID: 20579983, PMCID: PMC3657741, DOI: 10.1016/j.febslet.2010.06.016.Peer-Reviewed Original ResearchSNMIB/Apollo protects leading‐strand telomeres against NHEJ‐mediated repair
Lam YC, Akhter S, Gu P, Ye J, Poulet A, Giraud‐Panis M, Bailey SM, Gilson E, Legerski RJ, Chang S. SNMIB/Apollo protects leading‐strand telomeres against NHEJ‐mediated repair. The EMBO Journal 2010, 29: 2230-2241. PMID: 20551906, PMCID: PMC2905253, DOI: 10.1038/emboj.2010.58.Peer-Reviewed Original ResearchMeSH KeywordsAminopeptidasesAnimalsAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsChromosomesDipeptidyl-Peptidases and Tripeptidyl-PeptidasesDNA DamageDNA RepairDNA-Binding ProteinsEmbryo, MammalianExodeoxyribonucleasesFibroblastsMiceMice, KnockoutProtein Serine-Threonine KinasesSerine ProteasesShelterin ComplexTelomereTelomere-Binding ProteinsTripeptidyl-Peptidase 1Tumor Suppressor ProteinsConceptsMouse embryo fibroblastsNull mouse embryo fibroblastsNon-homologous end-joining pathwayLeading-strand DNA synthesisExonuclease functionSNM1B/ApolloDNA double-strand breaksDNA damage responseEnd-joining pathwayDouble-strand breaksMammalian telomeresUncapped telomeresNuclease domainNuclease familyDamage responseDNA replicationTelomeric endTelomeresNuclease activityAurora 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
2009
Pot1b Deletion and Telomerase Haploinsufficiency in Mice Initiate an ATR-Dependent DNA Damage Response and Elicit Phenotypes Resembling Dyskeratosis Congenita
He H, Wang Y, Guo X, Ramchandani S, Ma J, Shen MF, Garcia DA, Deng Y, Multani AS, You MJ, Chang S. Pot1b Deletion and Telomerase Haploinsufficiency in Mice Initiate an ATR-Dependent DNA Damage Response and Elicit Phenotypes Resembling Dyskeratosis Congenita. Molecular And Cellular Biology 2009, 29: 229-240. PMID: 18936156, PMCID: PMC2612488, DOI: 10.1128/mcb.01400-08.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtaxia Telangiectasia Mutated ProteinsBone Marrow CellsCell Cycle ProteinsCell DeathCell ProliferationDNA DamageDNA-Binding ProteinsDyskeratosis CongenitaGene DeletionHaploidyHematopoietic SystemMiceMice, KnockoutNucleic Acid ConformationOrgan SpecificityPhenotypeProtein Serine-Threonine KinasesSurvival AnalysisTelomeraseTelomereConceptsDisease dyskeratosis congenitaATR-dependent DNA damage responseDNA damage responseTelomerase haploinsufficiencyDamage responseBone marrow failureTelomeres 1 (POT1) proteinDyskeratosis congenitaProliferative tissueGenome integrityPOT1 functionChromosome endsMarrow failureEnd fusionsG-overhangsChromosome instabilityTelomerase deficiencyGerm cellsBinding proteinHematopoietic progenitorsStem cellsSurvival potentialEssential roleLong-term viabilityCellular viability
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 modelChromosomesDysfunctionProteinApoptosisInitiation of Genomic Instability, Cellular Senescence, and Organismal Aging by Dysfunctional Telomeres
Chang S. Initiation of Genomic Instability, Cellular Senescence, and Organismal Aging by Dysfunctional Telomeres. 2008, 57-75. DOI: 10.1007/978-3-540-73709-4_4.Peer-Reviewed Original ResearchDysfunctional telomeresOrganismal agingCellular senescenceDNA damage responseLinear chromosomesShelterin complexDamage responseTelomeric repeatsGenomic instabilityTelomeric structureTelomeresSenescenceFunction resultsProteinImportant roleChromosomesMouse modelRepeatsTelomeraseDNAProgressive lossP53ActivationComplexesAging
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 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 deletionBlock of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations
Haines BB, Ryu CJ, Chang S, Protopopov A, Luch A, Kang YH, Draganov DD, Fragoso MF, Paik SG, Hong HJ, DePinho RA, Chen J. Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations. Cancer Cell 2006, 9: 109-120. PMID: 16473278, DOI: 10.1016/j.ccr.2006.01.004.Peer-Reviewed Original Research