2024
TRF2–RAP1 represses RAD51-dependent homology-directed telomere repair by promoting BLM-mediated D-loop unwinding and inhibiting BLM–DNA2-dependent 5′-end resection
Liang F, Rai R, Sodeinde T, Chang S. TRF2–RAP1 represses RAD51-dependent homology-directed telomere repair by promoting BLM-mediated D-loop unwinding and inhibiting BLM–DNA2-dependent 5′-end resection. Nucleic Acids Research 2024, gkae642. PMID: 39082275, DOI: 10.1093/nar/gkae642.Peer-Reviewed Original ResearchHomology-directed repairTelomeric D-loopsD-loopChromosome fusionsD-loop formationSingle-stranded telomeric overhangsHomology searchTelomere clusteringTRFH domainPurified proteinBasic domainBlm mutantsProtect telomeresGenomic instabilityTelomeric overhangEnd resectionTRF2Molecular mechanismsTelomereTelomere lossMolecular pathwaysTelomere repairGenomeMutantsRap1
2023
Telomeres cooperate with the nuclear envelope to maintain genome stability
Rai R, Sodeinde T, Boston A, Chang S. Telomeres cooperate with the nuclear envelope to maintain genome stability. BioEssays 2023, 46: e2300184. PMID: 38047499, DOI: 10.1002/bies.202300184.Peer-Reviewed Original ResearchNuclear envelopeGenome stabilityNuclear envelope ruptureKu70/Ku80Homology-directed recombinationMammalian telomeresChromosome stabilityNuclear laminsShelterin componentsProtein TRF2Envelope ruptureRepair proteinsTelomeresRap1Recent findingsProteinFunction resultsRecombinationDNA sensingForm structuresLaminsTRF2Ku80DNAHomeostasisPot1b −/− 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 mechanismMutationsAuthor Correction: Homology 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. Author Correction: Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1. Nature Communications 2023, 14: 3319. PMID: 37286532, PMCID: PMC10247812, DOI: 10.1038/s41467-023-39144-7.Peer-Reviewed Original ResearchHomology 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-strandTPP1ProteinA Splendid Comet Graces the Northern Sky
Chang S. A Splendid Comet Graces the Northern Sky. Clinical Chemistry 2021, 67: 705-705. DOI: 10.1093/clinchem/hvaa229.Peer-Reviewed Original Research
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 portionMutationsDomainMutantsTelomeresCytogenetic 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