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 mechanismMutationsHomology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1
Rai R, Biju K, Sun W, Sodeinde T, Al-Hiyasat A, Morgan J, Ye X, Li X, Chen Y, Chang S. Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1. Nature Communications 2023, 14: 2144. PMID: 37059728, PMCID: PMC10104862, DOI: 10.1038/s41467-023-37761-w.Peer-Reviewed Original ResearchConceptsDouble-strand breaksNuclear envelopeDistinct DNA repair mechanismsNuclear envelope ruptureKu70/Ku80DNA repair mechanismsDNA-RNA hybridsBRCT domainGenome stabilityPhosphomimetic mutantTelomere formationGenotoxic stressEnvelope ruptureDysfunctional telomeresBasic domainRap1Aberrant laminTelomeresRepair mechanismsLaminsTRF2HomologyProteinShelterinADAR1p110
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
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 damageReplisomeClaspin
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 roleTRF1TelomeresCytogenetic Analysis of Telomere Dysfunction
Rai R, Multani AS, Chang S. Cytogenetic Analysis of Telomere Dysfunction. Methods In Molecular Biology 2017, 1587: 127-131. PMID: 28324504, DOI: 10.1007/978-1-4939-6892-3_12.Peer-Reviewed Original ResearchProbing 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 responseMalignancyDysfunctional telomeres induce p53‐dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation
Wang Y, Wang X, Flores ER, Yu J, Chang S. Dysfunctional telomeres induce p53‐dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell 2016, 15: 646-660. PMID: 27113195, PMCID: PMC4933665, DOI: 10.1111/acel.12476.Peer-Reviewed Original ResearchTRF2-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
Pot1a Prevents Telomere Dysfunction and ATM-Dependent Neuronal Loss
Lee Y, Brown EJ, Chang S, McKinnon PJ. Pot1a Prevents Telomere Dysfunction and ATM-Dependent Neuronal Loss. Journal Of Neuroscience 2014, 34: 7836-7844. PMID: 24899707, PMCID: PMC4044246, DOI: 10.1523/jneurosci.4245-13.2014.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornAtaxia Telangiectasia Mutated ProteinsBeta-GalactosidaseBrainCell CycleCell Cycle ProteinsCells, CulturedDNA DamageDNA-Binding ProteinsEmbryo, MammalianFemaleGene Expression RegulationMaleMiceMice, TransgenicNestinNeuronsShelterin ComplexTelomereTelomere-Binding Proteins
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 stabilizationCellsSLX4 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 mutationThe 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 approach