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
2020
Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly
Cicconi A, Rai R, Xiong X, Broton C, Al-Hiyasat A, Hu C, Dong S, Sun W, Garbarino J, Bindra RS, Schildkraut C, Chen Y, Chang S. Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly. Nature Communications 2020, 11: 5861. PMID: 33203878, PMCID: PMC7672075, DOI: 10.1038/s41467-020-19674-0.Peer-Reviewed Original ResearchAminopeptidasesAnimalsBinding SitesCalorimetryCell Cycle ProteinsCytoskeletal ProteinsDipeptidyl-Peptidases and Tripeptidyl-PeptidasesDNA DamageFibroblastsHeLa CellsHistonesHumansMiceMicrocephalyMutationProtein Interaction Domains and MotifsSerine ProteasesShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2Shelterin 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
The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function
Rai R, Gu P, Broton C, Kumar-Sinha C, Chen Y, Chang S. The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function. Cell Reports 2019, 29: 3708-3725.e5. PMID: 31825846, PMCID: PMC7001145, DOI: 10.1016/j.celrep.2019.11.012.Peer-Reviewed Original ResearchMeSH KeywordsAcid Anhydride HydrolasesAdaptor Proteins, Signal TransducingAminopeptidasesAnimalsCell Cycle ProteinsCell Line, TumorCells, CulturedCheckpoint Kinase 1Dipeptidyl-Peptidases and Tripeptidyl-PeptidasesDNA End-Joining RepairDNA Repair EnzymesDNA-Binding ProteinsDNA-Directed DNA PolymeraseExodeoxyribonucleasesHEK293 CellsHumansMiceMRE11 Homologue ProteinMultienzyme ComplexesProliferating Cell Nuclear AntigenSerine ProteasesShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2ConceptsReplication protein AReplisome complexPOT1-TPP1Dysfunctional telomeresDNA damage sensor MRE11-RAD50DNA damage checkpoint responseAlternative non-homologous endNon-homologous endMRN functionChromosome endsMre11-Rad50Checkpoint responseDNA-PKTelomeric overhangMre11 nucleaseTelomere repairEnd resectionRAD-51Repair pathwaysAtaxia telangiectasiaTelomeresC-strandDNA damageReplisomeClaspinWRN 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
2018
CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length
Gu P, Jia S, Takasugi T, Smith E, Nandakumar J, Hendrickson E, Chang S. CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length. Aging Cell 2018, 17: e12783. PMID: 29774655, PMCID: PMC6052479, DOI: 10.1111/acel.12783.Peer-Reviewed Original Research
2017
Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex
Hu C, Rai R, Huang C, Broton C, Long J, Xu Y, Xue J, Lei M, Chang S, Chen Y. Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. Cell Research 2017, 27: 1485-1502. PMID: 29160297, PMCID: PMC5717407, DOI: 10.1038/cr.2017.144.Peer-Reviewed Original ResearchConceptsShelterin complexTelomeric DNAStructure-based mutagenesis analysisProtein-protein interaction platformRepetitive DNA sequencesTelomere end protectionN-terminal domainMammalian telomeresChromosome endsTelomeric complexNucleoprotein complexesMutagenesis analysisEnd protectionDNA sequencesLike domainHeterodimer bindsTIN2Functional analysisMolecular mechanismsTRF2TPP1Stable assemblyEssential roleTRF1TelomeresStructural 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 portionMutationsDomainMutantsTelomeresProbing 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 deletionTelomeresDNAPathwayTRF2Chk2Chk1KinaseEffectorsNBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres
Rai R, Hu C, Broton C, Chen Y, Lei M, Chang S. NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres. Molecular Cell 2017, 65: 801-817.e4. PMID: 28216226, PMCID: PMC5639704, DOI: 10.1016/j.molcel.2017.01.016.Peer-Reviewed Original ResearchAminopeptidasesAtaxia Telangiectasia Mutated ProteinsBinding SitesCell Cycle ProteinsCyclin-Dependent Kinase 2Dipeptidyl-Peptidases and Tripeptidyl-PeptidasesDNA Breaks, Double-StrandedDNA End-Joining RepairDNA Repair EnzymesDNA-Binding ProteinsExodeoxyribonucleasesG1 PhaseG2 PhaseHCT116 CellsHumansInhibitor of Apoptosis ProteinsModels, MolecularNuclear ProteinsPhosphorylationProtein BindingProtein Interaction Domains and MotifsS PhaseSerine ProteasesShelterin ComplexStructure-Activity RelationshipTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2
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 responseMalignancyTRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions
Rai R, Chen Y, Lei M, Chang S. TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nature Communications 2016, 7: 10881. PMID: 26941064, PMCID: PMC4785230, DOI: 10.1038/ncomms10881.Peer-Reviewed Original ResearchConceptsRepressor/activator protein 1Telomere length controlTranscriptional gene regulationRepair of telomeresTelomere end protectionNon-homologous endActivator protein-1Myb domainChromosome fusionsYeast Rap1Gene regulationHDR pathwayEnd protectionBasic domainTelomere lossTelomeresHuman cellsHR factorsProtein 1Length controlPARP1Free fusionInappropriate processingTRF2Important role
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 inhibition
2013
SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres
Wan B, Yin J, Horvath K, Sarkar J, Chen Y, Wu J, Wan K, Lu J, Gu P, Yu EY, Lue NF, Chang S, Liu Y, Lei M. SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres. Cell Reports 2013, 4: 861-869. PMID: 24012755, PMCID: PMC4334113, DOI: 10.1016/j.celrep.2013.08.017.Peer-Reviewed Original ResearchConceptsTRFH domainRecombination-based telomere maintenanceTelomeric protein TRF2Nucleolytic resolutionTelomeric localizationMultiple endonucleasesPeptide-binding siteDNA metabolismProtein TRF2Telomere maintenanceSLX4TRF2Molecular mechanismsDNA structureHuman cellsTelomeresSLX1Protein levelsEndonucleaseMotifMus81ComplexesNucleaseXPFDomainFunctional 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 mutationCancer chromosomes going to POT1
Chang S. Cancer chromosomes going to POT1. Nature Genetics 2013, 45: 473-475. PMID: 23619786, PMCID: PMC4040961, DOI: 10.1038/ng.2617.Peer-Reviewed Original ResearchSingle 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 ResearchCooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis
Akbay EA, Peña CG, Ruder D, Michel JA, Nakada Y, Pathak S, Multani AS, Chang S, Castrillon DH. Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis. Oncogene 2012, 32: 2211-2219. PMID: 22689059, PMCID: PMC3636499, DOI: 10.1038/onc.2012.232.Peer-Reviewed Original ResearchMeSH KeywordsAneuploidyAnimalsCarcinoma, EndometrioidCell Transformation, NeoplasticDisease Models, AnimalDNA Breaks, Double-StrandedDNA-Binding ProteinsEndometrial NeoplasmsFemaleHumansMiceMice, TransgenicShelterin ComplexTelomere HomeostasisTelomere-Binding ProteinsTumor Cells, CulturedTumor Suppressor Protein p53ConceptsType II endometrial cancerEndometrial intraepithelial carcinomaEndometrial cancerEndometrial adenocarcinomaEndometrial carcinogenesisTelomerase-null miceProminent nuclear atypiaType II tumorsMulti-organ failureType II cancersInvasive endometrial adenocarcinomaMonths of ageMetastatic diseaseII tumorsEndometrial lesionsIntraepithelial carcinomaEndometrial epitheliumNuclear atypiaTumorsAdenocarcinomaVivo correlatesDetectable DNA damageHuman tumorsMiceLesions