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
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 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
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 mutationSingle 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
CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion
Gu P, Min J, Wang Y, Huang C, Peng T, Chai W, Chang S. CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. The EMBO Journal 2012, 31: 2309-2321. PMID: 22531781, PMCID: PMC3364752, DOI: 10.1038/emboj.2012.96.Peer-Reviewed Original ResearchConceptsMammalian CSTTelomere lossDefective telomere replicationDeletion resultsG2/M checkpointComplete bone marrow failureStem cell exhaustionTelomere deprotectionGenome stabilityTEN1 (CST) complexTelomere replicationReplication forksTelomere maintenanceLength maintenanceCTC1-STN1Efficient restartM checkpointVivo functionCTC1TelomeresAcute deletionBone marrow failureProliferative defectEfficient replicationEssential role
2011
miRNA Regulatory Circuits in ES Cells Differentiation: A Chemical Kinetics Modeling Approach
Luo Z, Xu X, Gu P, Lonard D, Gunaratne PH, Cooney AJ, Azencott R. miRNA Regulatory Circuits in ES Cells Differentiation: A Chemical Kinetics Modeling Approach. PLOS ONE 2011, 6: e23263. PMID: 22039400, PMCID: PMC3198445, DOI: 10.1371/journal.pone.0023263.Peer-Reviewed Original ResearchConceptsES cell differentiationMRNA genesRepressive interactionsCell differentiationTarget mRNA genesEmbryonic stem cellsGene regulationRegulatory circuitsTranslation inhibitionMRNA targetsGene MES cellsMiRNAs inhibitorsMicroarray dataGenesMiRNAsStem cellsGene GProtein expressionDirect degradationMRNADifferentiationImportant roleCellsMicroRNAsDifferential Recruitment of Methyl CpG‐Binding Domain Factors and DNA Methyltransferases by the Orphan Receptor Germ Cell Nuclear Factor Initiates the Repression and Silencing of Oct4
Gu P, Xu X, Le Menuet D, Chung A, Cooney AJ. Differential Recruitment of Methyl CpG‐Binding Domain Factors and DNA Methyltransferases by the Orphan Receptor Germ Cell Nuclear Factor Initiates the Repression and Silencing of Oct4. Stem Cells 2011, 29: 1041-1051. PMID: 21608077, PMCID: PMC3468724, DOI: 10.1002/stem.652.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCell DifferentiationCell Line, TumorCpG IslandsDNA (Cytosine-5-)-MethyltransferasesDNA MethylationDNA Methyltransferase 3ADNA-Binding ProteinsEmbryonic Stem CellsGene Expression Regulation, DevelopmentalGene Knockdown TechniquesMiceMolecular Sequence DataNuclear Receptor Subfamily 6, Group A, Member 1Octamer Transcription Factor-3Promoter Regions, GeneticProtein BindingTranscription FactorsConceptsGerm cell nuclear factorEmbryonic stem cellsOct4 promoterDNA methylationDNA methyltransferasesRepressive functionEpigenetic modificationsTranscription factorsProximal promoterDifferentiation of ESCsWild-type embryonic stem cellsDe novo DnmtsGene-specific repressionKey transcription factorDifferential recruitmentNuclear factorGCNF bindsESC differentiationPluripotency genesOct4 geneSomatic cellsMethyl-CpGCis elementsMBD3Gene expression
2010
SNMIB/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 activityEvolutionary trace-based peptides identify a novel asymmetric interaction that mediates oligomerization in nuclear receptors.
Gu P, Morgan D, Sattar M, Xu X, Wagner R, Raviscioni M, Lichtarge O, Cooney A. Evolutionary trace-based peptides identify a novel asymmetric interaction that mediates oligomerization in nuclear receptors. Journal Of Biological Chemistry 2010, 285: 15662. PMCID: PMC2865313, DOI: 10.1074/jbc.a109.501924.Peer-Reviewed Original Research
2008
Novel MicroRNA Candidates and miRNA-mRNA Pairs in Embryonic Stem (ES) Cells
Gu P, Reid J, Gao X, Shaw C, Creighton C, Tran P, Zhou X, Drabek R, Steffen D, Hoang D, Weiss M, Naghavi A, El-daye J, Khan M, Legge G, Wheeler D, Gibbs R, Miller J, Cooney A, Gunaratne P. Novel MicroRNA Candidates and miRNA-mRNA Pairs in Embryonic Stem (ES) Cells. PLOS ONE 2008, 3: e2548. PMID: 18648548, PMCID: PMC2481296, DOI: 10.1371/journal.pone.0002548.Peer-Reviewed Original ResearchConceptsMiRNA-mRNA pairsEmbryonic stem cellsES cellsMiRNA candidatesPost-transcriptional gene regulationTranscriptional gene regulationCore regulatory networkLoss of repressionMiRNA target predictionOpposite expression trendsStem cellsES cell differentiationNovel candidatesNovel miRNAsGene regulationSmall RNAsMiRNA maturationGene networksTranscript sequencesRegulatory networksExpression trendsSilico searchMicroRNA candidatesCell differentiationTarget predictionNanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells
Liang J, Wan M, Zhang Y, Gu P, Xin H, Jung SY, Qin J, Wong J, Cooney AJ, Liu D, Songyang Z. Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nature Cell Biology 2008, 10: 731-739. PMID: 18454139, DOI: 10.1038/ncb1736.Peer-Reviewed Original ResearchConceptsES cell fateRepression complexMouse ES cellsCell fateTranscription factorsES cellsTranscriptional repression complexES cell differentiationEssential transcription factorEmbryonic stem cellsSub-stoichiometric levelsHistone deacetylase activityNuRD complexRepressor complexEndogenous NanogProtein complexesGene transcriptionTarget genesDeacetylase activityNanogNuRDGenesStem cellsCellsComplexes
2007
Nuclear Receptors in Regulation of Mouse ES Cell Pluripotency and Differentiation
Mullen EM, Gu P, Cooney AJ. Nuclear Receptors in Regulation of Mouse ES Cell Pluripotency and Differentiation. PPAR Research 2007, 2007: 61563. PMID: 18274628, PMCID: PMC2233893, DOI: 10.1155/2007/61563.Peer-Reviewed Original ResearchNuclear receptorsES cellsES cell phenotypeES cell pluripotencyLIF/STAT3Embryonic stem cellsTranscription factor Sox2Different cell typesCell pluripotencyPluripotent phenotypeFactor Sox2Differentiated cellsCell typesStem cellsCell phenotypeGreat therapeutic potentialPhenotypeCellsDifferentiationReceptorsImportant processPluripotency
2005
Orphan Nuclear Receptor GCNF Is Required for the Repression of Pluripotency Genes during Retinoic Acid-Induced Embryonic Stem Cell Differentiation
Gu P, LeMenuet D, Chung A, Mancini M, Wheeler DA, Cooney AJ. Orphan Nuclear Receptor GCNF Is Required for the Repression of Pluripotency Genes during Retinoic Acid-Induced Embryonic Stem Cell Differentiation. Molecular And Cellular Biology 2005, 25: 8507-8519. PMID: 16166633, PMCID: PMC1265758, DOI: 10.1128/mcb.25.19.8507-8519.2005.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, NorthernBlotting, WesternCell DifferentiationCell LineCell NucleusChromatin ImmunoprecipitationDNA-Binding ProteinsDown-RegulationEmbryo, MammalianFemaleFibroblast Growth Factor 4GenotypeHomeodomain ProteinsIn Situ HybridizationMaleMiceMice, TransgenicMicroscopy, FluorescenceModels, GeneticNanog Homeobox ProteinNuclear Receptor Subfamily 6, Group A, Member 1Octamer Transcription Factor-3PhenotypePlasmidsProtein BindingReceptors, Cytoplasmic and NuclearResponse ElementsReverse Transcriptase Polymerase Chain ReactionSignal TransductionSOXB1 Transcription FactorsStem CellsTime FactorsTrans-ActivatorsTransfectionTretinoinConceptsLoss of repressionES cell differentiationPluripotency genesCell differentiationTranscription factorsEmbryonic developmentES cellsEmbryonic stem cell pluripotencyEmbryonic stem cell differentiationEarly mouse embryonic developmentStem cell pluripotencyMouse embryonic developmentPluripotency gene expressionEarly embryonic developmentInitiation of differentiationStem cell differentiationRetinoic acidCell pluripotencyNanog geneGenes Oct4Somatic cellsUndifferentiated stateGene expressionGCNFRepressionCorrelated Evolutionary Pressure at Interacting Transcription Factors and DNA Response Elements Can Guide the Rational Engineering of DNA Binding Specificity
Raviscioni M, Gu P, Sattar M, Cooney AJ, Lichtarge O. Correlated Evolutionary Pressure at Interacting Transcription Factors and DNA Response Elements Can Guide the Rational Engineering of DNA Binding Specificity. Journal Of Molecular Biology 2005, 350: 402-415. PMID: 15946684, DOI: 10.1016/j.jmb.2005.04.054.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiological EvolutionComputational BiologyDNADNA Mutational AnalysisDNA-Binding ProteinsEntropyEvolution, MolecularGenomicsHumansModels, GeneticModels, StatisticalMutationNucleic Acid ConformationPhylogenyProtein BindingProtein EngineeringReceptors, Cytoplasmic and NuclearReceptors, EstrogenResponse ElementsSoftwareThermodynamicsTranscription FactorsConceptsDNA binding specificityTranscription factorsBinding specificityEvolutionary importanceEvolutionary pressureResponse elementInteracting Transcription FactorsRational engineeringRelative evolutionary importanceProtein-DNA interfaceProtein-DNA interactionsTranscription factor proteinsDNA response elementsAmino acid residuesNuclear hormone receptorsTranscriptional regulatorsEvolutionary traceImportant residuesGene expressionRecognition codeMolecular mechanismsAcid residuesFactor proteinProtein residuesLRH-1