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
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
TRF2-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
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 ProteinsProbing the Telomere Damage Response
Rai R, Chang S. Probing the Telomere Damage Response. Methods In Molecular Biology 2011, 735: 145-150. PMID: 21461819, PMCID: PMC3690558, DOI: 10.1007/978-1-61779-092-8_14.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 deletionTelomeresDNAPathwayTRF2Chk2Chk1KinaseEffectorsA conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms
Chen Y, Rai R, Zhou ZR, Kanoh J, Ribeyre C, Yang Y, Zheng H, Damay P, Wang F, Tsujii H, Hiraoka Y, Shore D, Hu HY, Chang S, Lei M. A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms. Nature Structural & Molecular Biology 2011, 18: 213-221. PMID: 21217703, PMCID: PMC3688267, DOI: 10.1038/nsmb.1974.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAmino Acid SequenceAnimalsCells, CulturedCrystallography, X-RayFungal ProteinsHeLa CellsHumansModels, MolecularMolecular Sequence DataMutationNuclear Magnetic Resonance, BiomolecularProtein BindingProtein Interaction Domains and MotifsSaccharomycetalesSchizosaccharomycesShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2ConceptsRap1 C-terminusDifferent interacting partnersProtein Rap1Fission yeastTelomere protectionInteracting partnerTranscriptional silencingDifferent organismsC-terminusFunctional analysisInteraction moduleYeastRap1Different functionsOrganismsTaz1Sir3TRF2MammalianTelomeresSilencingMammalsMotifCrystal structureRegulation
2010
The function of classical and alternative non‐homologous end‐joining pathways in the fusion of dysfunctional telomeres
Rai R, Zheng H, He H, Luo Y, Multani A, Carpenter PB, Chang S. The function of classical and alternative non‐homologous end‐joining pathways in the fusion of dysfunctional telomeres. The EMBO Journal 2010, 29: 2598-2610. PMID: 20588252, PMCID: PMC2928694, DOI: 10.1038/emboj.2010.142.Peer-Reviewed Original ResearchAnimalsAntigens, NuclearCells, CulturedChromosomal Proteins, Non-HistoneDNA RepairDNA-Binding ProteinsHumansIntracellular Signaling Peptides and ProteinsKu AutoantigenMiceMice, KnockoutShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2Tumor Suppressor p53-Binding Protein 1
2008
Differential regulation of centrosome integrity by DNA damage response proteins
Rai R, Phadnis A, Haralkar S, Badwe RA, Dai H, Li K, Lin SY. Differential regulation of centrosome integrity by DNA damage response proteins. Cell Cycle 2008, 7: 2225-2233. PMID: 18635967, PMCID: PMC2557875, DOI: 10.4161/cc.7.14.6303.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAurora KinasesBreast NeoplasmsCell Cycle ProteinsCell Line, TumorCentrosomeCytokinesisCytoskeletal ProteinsDisease ProgressionDNA DamageFemaleHumansMitosisModels, BiologicalNerve Tissue ProteinsNuclear ProteinsProtein Serine-Threonine KinasesProtein TransportProto-Oncogene ProteinsSpindle ApparatusTrans-ActivatorsConceptsCentrosome integritySpindle assemblyCentrosome duplicationDNA damage response proteinsProper centrosome duplicationDamage response proteinsMitotic spindle assemblySpindle checkpoint activationTumor suppressor geneDefective mitosisChromosome missegregationCentrosomal kinaseDefective cytokinesisCheckpoint activationCentrosome maturationNovel functionResponse proteinsBRIT1MDC1Key regulatorNegative regulatorAurora ACentrosome overduplicationDifferential regulationDNA damage
2007
DNA damage response: the players, the network and the role in tumor suppression.
Rai R, Peng G, Li K, Lin SY. DNA damage response: the players, the network and the role in tumor suppression. Cancer Genomics & Proteomics 2007, 4: 99-106. PMID: 17804872.Peer-Reviewed Original ResearchConceptsDNA damage responseDamage responseDNA-damaging insultsCell cycle checkpointsDNA damage lesionsGenomic integrityCycle checkpointsDNA repairGenomic instabilityTumor suppressionMolecular eventsGenetic instabilityDNA damageDamage lesionsCancer developmentNormal cellsComplex mechanismsCommon featureCheckpointTumorigenesisPathwayResponseCells
2006
BRIT1/MCPH1: A Guardian of Genome and an Enemy of Tumors
Chaplet M, Rai R, Jackson-Bernitsas D, Li K, Lin SY. BRIT1/MCPH1: A Guardian of Genome and an Enemy of Tumors. Cell Cycle 2006, 5: 2579-2583. PMID: 17172830, DOI: 10.4161/cc.5.22.3471.Peer-Reviewed Original ResearchConceptsDNA damageTiming of mitosisDNA damage checkpointDNA damage responseCell cycle checkpointsGuardian of genomePotential tumor suppressorDamage checkpointEukaryotic cellsIntriguing proteinNuclear fociGenomic stabilityDamage responseCycle checkpointsBRIT1Damage sensorTumor suppressorCellular responsesSophisticated mechanismsCancer initiationCentrosomal abnormalitiesNeoplastic transformationGenomeProteinImportant moleculesBRIT1 regulates early DNA damage response, chromosomal integrity, and cancer
Rai R, Dai H, Multani AS, Li K, Chin K, Gray J, Lahad JP, Liang J, Mills GB, Meric-Bernstam F, Lin SY. BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer. Cancer Cell 2006, 10: 145-157. PMID: 16872911, PMCID: PMC1557410, DOI: 10.1016/j.ccr.2006.07.002.Peer-Reviewed Original ResearchMeSH KeywordsBase SequenceBreast NeoplasmsCell Cycle ProteinsCell Line, TumorCell NucleusCell Transformation, NeoplasticChromatinChromosome AberrationsCytoskeletal ProteinsDNA DamageFemaleGene DosageHumansMolecular Sequence DataMutationNerve Tissue ProteinsNuclear ProteinsOvarian NeoplasmsTrans-ActivatorsTumor Suppressor ProteinsConceptsATM/ATR pathwayDNA damage response pathwayEarly DNA damage responseDNA damage regulatorDNA damage checkpointDamage response pathwayDNA damage responseTumor suppressor geneHTERT repressorDamage checkpointATR pathwayDamage responseResponse pathwaysBRIT1Chromosomal integrityGenomic instabilitySuppressor geneHuman cancersAdditional functionsChromosomal aberrationsPathwayMDC1NBS1RepressorGenes
2005
BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1–Chk1 pathway, implicating checkpoint dysfunction in microcephaly
Lin SY, Rai R, Li K, Xu ZX, Elledge SJ. BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1–Chk1 pathway, implicating checkpoint dysfunction in microcephaly. Proceedings Of The National Academy Of Sciences Of The United States Of America 2005, 102: 15105-15109. PMID: 16217032, PMCID: PMC1257745, DOI: 10.1073/pnas.0507722102.Peer-Reviewed Original ResearchConceptsDNA damage responsive proteinBRIT1/MCPH1Human telomerase functionDamage-responsive proteinsChromatin-associated proteinsPhosphorylation of Nbs1Checkpoint kinase Chk1G2/M checkpointSeckel syndrome patientsCell cycle arrestGamma-H2AX fociKinase Chk1Nuclear fociResponsive proteinsTelomerase functionMicrocephaly disordersMCPH1 geneCellular immortalizationBRIT1MCPH1 deficiencyChk1 pathwayAtaxia telangiectasiaM checkpointPrimary microcephalyChk1
2004
Genome wide instability scanning in chewing-tobacco associated oral cancer using inter simple sequence repeat PCR
Rai R, Kulkarni V, Saranath D. Genome wide instability scanning in chewing-tobacco associated oral cancer using inter simple sequence repeat PCR. Oral Oncology 2004, 40: 1033-1039. PMID: 15509495, DOI: 10.1016/j.oraloncology.2004.05.009.Peer-Reviewed Original ResearchConceptsOral cancerTumor tissueNormal tissuesOral cancer patientsTumor-adjacent normal tissuesOral cancer samplesAdjacent normal tissuesMultiple tumor tissuesCancer patientsNormal tissue DNATumor progressionCancer samplesGenomic instability indexCancerTissue DNAGenomic alterationsTumor heterogeneityGenomic instabilityTissueMolecular cloning, isolation and characterisation of ERK3 gene from chewing-tobacco induced oral squamous cell carcinoma
Rai R, Mahale A, Saranath D. Molecular cloning, isolation and characterisation of ERK3 gene from chewing-tobacco induced oral squamous cell carcinoma. Oral Oncology 2004, 40: 705-712. PMID: 15172640, DOI: 10.1016/j.oraloncology.2004.01.010.Peer-Reviewed Original ResearchMeSH KeywordsBase SequenceBlotting, NorthernBlotting, SouthernCarcinoma, Squamous CellCloning, MolecularDNA, ComplementaryDNA, NeoplasmGene ExpressionGene LibraryHumansMitogen-Activated Protein Kinase 6Mitogen-Activated Protein KinasesMolecular Sequence DataMouth NeoplasmsReverse Transcriptase Polymerase Chain ReactionTobacco, SmokelessConceptsOral cancer tissuesOral squamous cell carcinomaSquamous cell carcinomaPeripheral blood cellsNormal healthy individualsCancer tissuesExtracellular signal-regulated protein kinaseCell carcinomaOral cancerHealthy individualsNon-coding regionBlood cellsSerine/threonine kinaseSignal-regulated protein kinaseTobacco habitsC-Jun N-terminal kinaseFetal skeletal muscleMRNA transcript analysisNormal individualsN-terminal kinaseRegulation of mRNAPatient samplesRT-PCR analysisSkeletal muscleERK3 expression