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 2
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
2017
Probing 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
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
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 ResearchRPA and POT1
Flynn RL, Chang S, Zou L. RPA and POT1. Cell Cycle 2012, 11: 652-657. PMID: 22373525, PMCID: PMC3318101, DOI: 10.4161/cc.11.4.19061.Peer-Reviewed Original ResearchConceptsReplication protein ATelomere maintenanceDNA replicationProtein complex shelterinTTAGGG telomeric repeatsTelomeric ssDNACheckpoint responseTelomeric repeatsPOT1Ataxia telangiectasiaCell cycleAberrant accumulationCycling cellsSpecific mannerInteresting modelTelomeresProtein ACritical roleProteinRecent studiesReplicationShelterinRad3KinaseRepeats
2011
TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA
Flynn RL, Centore RC, O’Sullivan R, Rai R, Tse A, Songyang Z, Chang S, Karlseder J, Zou L. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature 2011, 471: 532-536. PMID: 21399625, PMCID: PMC3078637, DOI: 10.1038/nature09772.Peer-Reviewed Original ResearchAtaxia Telangiectasia Mutated ProteinsBinding, CompetitiveCell Cycle ProteinsCell ExtractsDNA ReplicationDNA, Single-StrandedHeLa CellsHeterogeneous Nuclear Ribonucleoprotein A1Heterogeneous-Nuclear Ribonucleoprotein Group A-BHumansProtein BindingReplication Protein ARNAS PhaseShelterin ComplexTelomereTelomere-Binding ProteinsThe RAG2 C terminus suppresses genomic instability and lymphomagenesis
Deriano L, Chaumeil J, Coussens M, Multani A, Chou Y, Alekseyenko AV, Chang S, Skok JA, Roth DB. The RAG2 C terminus suppresses genomic instability and lymphomagenesis. Nature 2011, 471: 119-123. PMID: 21368836, PMCID: PMC3174233, DOI: 10.1038/nature09755.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsChromosome DeletionChromosomes, MammalianDisease ProgressionDNA-Binding ProteinsGene Rearrangement, T-LymphocyteGenes, Immunoglobulin Heavy ChainGenes, p53Genomic InstabilityIn Situ Hybridization, FluorescenceKaplan-Meier EstimateLymphomaMiceProtein Serine-Threonine KinasesReceptors, Antigen, T-CellRecombination, GeneticThymus GlandTranslocation, GeneticTumor Suppressor ProteinsConceptsRAG2 C terminusGenomic instabilityC-terminusTCRα/δDNA double-strand breaksT-cell receptor lociDouble-strand breaksGenomic stabilityComplex chromosomal translocationReceptor locusChromosomal translocationsSimilar defectsLymphomagenesisThymic lymphomasTerminusLociRecombinaseTailRAG2TranslocationDeletionRecombinationRoleLymphoid malignanciesMice
2010
The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development
Akhter S, Lam YC, Chang S, Legerski RJ. The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development. Aging Cell 2010, 9: 1047-1056. PMID: 20854421, PMCID: PMC3719988, DOI: 10.1111/j.1474-9726.2010.00631.x.Peer-Reviewed Original ResearchConceptsMutant mouse embryonic fibroblastsSNM1B/ApolloCell proliferation defectMouse embryonic fibroblastsNormal cell proliferationDevelopmental failureHomozygous null miceEnd fusionsProliferation defectEmbryonic developmentGenomic instabilityEmbryonic fibroblastsTelomeric endDevelopmental defectsCell deathVivo roleCell proliferationImpaired proliferationTelomeresNull miceMutant miceSNMIB/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 activityBRIT1/MCPH1 Is Essential for Mitotic and Meiotic Recombination DNA Repair and Maintaining Genomic Stability in Mice
Liang Y, Gao H, Lin S, Peng G, Huang X, Zhang P, Goss J, Brunicardi F, Multani A, Chang S, Li K. BRIT1/MCPH1 Is Essential for Mitotic and Meiotic Recombination DNA Repair and Maintaining Genomic Stability in Mice. PLOS Genetics 2010, 6: e1000826. PMID: 20107607, PMCID: PMC2809772, DOI: 10.1371/journal.pgen.1000826.Peer-Reviewed Original ResearchConceptsMouse embryonic fibroblastsDNA double-strand breaksDNA repairGenomic stabilityDNA damage response pathwayBRIT1/MCPH1Meiotic homologous recombinationDNA damage signalingDamage response pathwayRecruitment of RAD51Localization of RAD51Novel key regulatorRAD51 foci formationDouble-strand breaksIrradiation-induced DNA damagePrimary microcephaly patientsBRCT domainMutant spermatocytesBRCA2 complexMCPH1 functionDamage signalingMeiotic chromosomesChromosomal synapsisProphase IResponse pathways
2009
Multiple roles for MRE11 at uncapped telomeres
Deng Y, Guo X, Ferguson DO, Chang S. Multiple roles for MRE11 at uncapped telomeres. Nature 2009, 460: 914-918. PMID: 19633651, PMCID: PMC2760383, DOI: 10.1038/nature08196.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsAtaxia Telangiectasia Mutated ProteinsATP-Binding Cassette TransportersCell Cycle ProteinsCell LineChromosomal Proteins, Non-HistoneChromosome AberrationsDNA DamageDNA Ligase ATPDNA LigasesDNA Repair EnzymesDNA-Binding ProteinsFibroblastsIntracellular Signaling Peptides and ProteinsMiceMRE11 Homologue ProteinNuclear ProteinsShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2Tumor Suppressor p53-Binding Protein 1Tumor Suppressor ProteinsConceptsMRN complexLinear eukaryotic chromosomesDNA double-strand breaksDNA damage repair pathwaysDouble-strand breaksDamage repair pathwaysGenome integrityEukaryotic chromosomesUncapped telomeresTelomere maintenanceRepair factorsDNA endsRepair pathwaysTelomeric endNuclease activityTelomeresMultiple rolesMre11Major playersPathogenic lesionsMre1ChromosomesComplexesProteinAllelesPot1b 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
Mre11 Nuclease Activity Has Essential Roles in DNA Repair and Genomic Stability Distinct from ATM Activation
Buis J, Wu Y, Deng Y, Leddon J, Westfield G, Eckersdorff M, Sekiguchi JM, Chang S, Ferguson DO. Mre11 Nuclease Activity Has Essential Roles in DNA Repair and Genomic Stability Distinct from ATM Activation. Cell 2008, 135: 85-96. PMID: 18854157, PMCID: PMC2645868, DOI: 10.1016/j.cell.2008.08.015.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsCell Line, TransformedCell ProliferationDNA Breaks, Double-StrandedDNA DamageDNA RepairDNA Repair EnzymesDNA-Binding ProteinsFibroblastsGenomic InstabilityMiceMRE11 Homologue ProteinProtein Serine-Threonine KinasesRecombination, GeneticTelomereTumor Suppressor ProteinsConceptsMre11/Rad50/Nbs1Nuclease activityDNA repairDNA damageDramatic genomic instabilityFunctions of Mre11Early embryonic lethalityMre11 nuclease activityATM kinaseATR kinaseEmbryonic lethalityGenomic stabilityATM activationMRN complexNucleolytic processingBreak repairDNA endsATM signalingMouse alleleGenomic instabilityDNA nuclease activityNuclease deficienciesEssential functionsUnknown roleMre11Control of chromosome stability by the β-TrCP–REST–Mad2 axis
Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Multani AS, Cardozo T, Lasorella A, Iavarone A, Chang S, Hernando E, Pagano M. Control of chromosome stability by the β-TrCP–REST–Mad2 axis. Nature 2008, 452: 365-369. PMID: 18354482, PMCID: PMC2707768, DOI: 10.1038/nature06641.Peer-Reviewed Original ResearchMeSH KeywordsBeta-Transducin Repeat-Containing ProteinsCalcium-Binding ProteinsCell Cycle ProteinsCell LineChromosomal InstabilityG2 PhaseGene Expression RegulationGenomic InstabilityHumansMad2 ProteinsMitosisProtein BindingRepressor ProteinsSKP Cullin F-Box Protein LigasesSpindle ApparatusTranscription Factors
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 Proteins
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
2004
Tumor-Specific Low Molecular Weight Forms of Cyclin E Induce Genomic Instability and Resistance to p21, p27, and Antiestrogens in Breast Cancer
Akli S, Zheng PJ, Multani AS, Wingate HF, Pathak S, Zhang N, Tucker SL, Chang S, Keyomarsi K. Tumor-Specific Low Molecular Weight Forms of Cyclin E Induce Genomic Instability and Resistance to p21, p27, and Antiestrogens in Breast Cancer. Cancer Research 2004, 64: 3198-3208. PMID: 15126360, DOI: 10.1158/0008-5472.can-03-3672.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAnimalsBreast NeoplasmsCDC2-CDC28 KinasesCell Cycle ProteinsCell DivisionCell Line, TumorCyclin ECyclin-Dependent Kinase 2Cyclin-Dependent Kinase Inhibitor p21Cyclin-Dependent Kinase Inhibitor p27CyclinsEstradiolEstrogen Receptor ModulatorsFemaleFulvestrantG1 PhaseGenomic InstabilityHumansMiddle AgedMolecular WeightPolyploidyProtein IsoformsTransfectionTumor Suppressor ProteinsConceptsBreast cancer patientsPoor outcomeCancer patientsBreast cancerCyclin ELMW formsPoor clinical outcomeEffects of antiestrogensPotential therapeutic targetLow molecular weight isoformsCyclin-dependent kinase inhibitor p21Clinical outcomesAggressive diseaseSurrogate markerDisease progressionPathobiological mechanismsTherapeutic targetMolecular weight isoformsPatientsTumor cellsLMW isoformsTumorsPowerful predictorLow molecular weight formWeight isoforms
2001
Rescue of a telomere length defect of Nijmegen breakage syndrome cells requires NBS and telomerase catalytic subunit
Ranganathan V, Heine W, Ciccone D, Rudolph K, Wu X, Chang S, Hai H, Ahearn I, Livingston D, Resnick I, Rosen F, Seemanova E, Jarolim P, DePinho R, Weaver D. Rescue of a telomere length defect of Nijmegen breakage syndrome cells requires NBS and telomerase catalytic subunit. Current Biology 2001, 11: 962-966. PMID: 11448772, DOI: 10.1016/s0960-9822(01)00267-6.Peer-Reviewed Original ResearchConceptsNijmegen breakage syndromeNBS fibroblastsNBS patientsCatalytic subunitChromosome instabilityNijmegen breakage syndrome cellsDNA repair complexRare human diseasesTRF proteinsTelomere extensionNBS cellsTelomere endsRepair complexAccessory proteinsBreakage syndromeGrowth cessationHuman diseasesCancer predispositionLength defectsTelomeresPremature growth cessationProliferative capacitySubunitsProteinGamma irradiation damage