2024
Next-generation cell-penetrating antibodies for tumor targeting and RAD51 inhibition
Rackear M, Quijano E, Ianniello Z, Colón-Ríos D, Krysztofiak A, Abdullah R, Liu Y, Rogers F, Ludwig D, Dwivedi R, Bleichert F, Glazer P. Next-generation cell-penetrating antibodies for tumor targeting and RAD51 inhibition. Oncotarget 2024, 15: 699-713. PMID: 39352803, PMCID: PMC11444335, DOI: 10.18632/oncotarget.28651.Peer-Reviewed Original ResearchConceptsTumor targetingMonoclonal antibody therapyTumor-specific targetingCell uptakeNucleic acid bindingCell surface antigensAntibody therapyHuman variantsClinical successCell-penetrating antibodiesAcid bindingSystemic administrationSurface antigensTumorRAD51 inhibitionAntibody platformMechanism of cell penetrationBind RAD51AntibodiesFull-lengthSpecific targetsCell penetrationDisease targetsCellsAutoantibodies
2023
A dual role for the chromatin reader ORCA/LRWD1 in targeting the origin recognition complex to chromatin
Sahu S, Ekundayo B, Kumar A, Bleichert F. A dual role for the chromatin reader ORCA/LRWD1 in targeting the origin recognition complex to chromatin. The EMBO Journal 2023, 42: embj2023114654. PMID: 37551430, PMCID: PMC10505921, DOI: 10.15252/embj.2023114654.Peer-Reviewed Original ResearchConceptsOrigin recognition complexH4K20 trimethylationHeterochromatin replicationRecognition complexCryo-electron microscopy structureLocal chromatin environmentSpecific histone marksSpecific chromatin contextsMcm2-7 loadingTernary complex assemblyChromatin environmentChromatin marksChromatin contextHistone marksHistone modificationsReplication initiationEukaryotic cellsMicroscopy structureChromatin condensatesORC recruitmentDNA replicationMammalian cellsNucleosomal DNAAromatic cageComplex assembly
2022
A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6
Schmidt JM, Yang R, Kumar A, Hunker O, Seebacher J, Bleichert F. A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6. Nature Communications 2022, 13: 1059. PMID: 35217664, PMCID: PMC8881611, DOI: 10.1038/s41467-022-28695-w.Peer-Reviewed Original ResearchConceptsOrigin recognition complexS. cerevisiaeCyclin-dependent kinase phosphorylationMcm2-7 loadingN-terminal domainCryo-electron microscopyCDK phosphorylationRecognition complexDNA replicationReplication originsÅ resolutionKinase phosphorylationMechanism of originCdc6Coordinated actionCerevisiaePhosphorylationDNAInhibitory signalsStructural detailsSite regulationRecruitmentOrc6AssemblyCdt1
2020
Structural mechanism for replication origin binding and remodeling by a metazoan origin recognition complex and its co-loader Cdc6
Schmidt JM, Bleichert F. Structural mechanism for replication origin binding and remodeling by a metazoan origin recognition complex and its co-loader Cdc6. Nature Communications 2020, 11: 4263. PMID: 32848132, PMCID: PMC7450096, DOI: 10.1038/s41467-020-18067-7.Peer-Reviewed Original ResearchMeSH KeywordsAAA DomainAdenosine TriphosphateAnimalsCell Cycle ProteinsCryoelectron MicroscopyDNADrosophila melanogasterDrosophila ProteinsHydrolysisMinichromosome Maintenance ProteinsModels, MolecularOrigin Recognition ComplexProtein BindingRecombinant ProteinsReplication OriginSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsConceptsOrigin recognition complexRecognition complexReplication originsDrosophila origin recognition complexEukaryotic DNA replication initiationMetazoan origin recognition complexCryo-electron microscopy structureMcm2-7 replicative helicaseATPase siteDNA replication initiationWalker B motifMcm2-7 loadingWinged-helix domainReplicative helicaseReplication initiationMicroscopy structureDistinct DNAB motifOrigin recognitionDNA sequencesDNA bendingDNA bindingPrimary DNADNA geometryLoop region
2019
Mechanisms of replication origin licensing: a structural perspective
Bleichert F. Mechanisms of replication origin licensing: a structural perspective. Current Opinion In Structural Biology 2019, 59: 195-204. PMID: 31630057, DOI: 10.1016/j.sbi.2019.08.007.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsReplicative helicasesKey cell cycle eventsReplication origin licensingReplication start sitesCell cycle eventsOrigin licensingReplicative helicaseReplication initiationInitiation factorsStart siteChromosomal DNAReplicative machineryCycle eventsMolecular approachesSynthesis apparatusHelicasesMachineryStructural perspectiveBidirectional mannerDNAEukaryotesHelicaseRecent advancesDuplicationMechanismOrigins of DNA replication
Ekundayo B, Bleichert F. Origins of DNA replication. PLOS Genetics 2019, 15: e1008320. PMID: 31513569, PMCID: PMC6742236, DOI: 10.1371/journal.pgen.1008320.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsKingdoms of lifeDomains of lifeDaughter cellsDNA replicationReplication originsCell divisionAccurate duplicationDaughter strandsGenomic DNAHereditary informationSemiconservative replicationGenetic materialFull complementDNA synthesisDiscrete sitesDNABidirectional mannerReplicationDivergent strategiesChromosomesOrganismsDuplicationOriginCellsStrands
2018
Conformational control and DNA-binding mechanism of the metazoan origin recognition complex
Bleichert F, Leitner A, Aebersold R, Botchan MR, Berger JM. Conformational control and DNA-binding mechanism of the metazoan origin recognition complex. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: e5906-e5915. PMID: 29899147, PMCID: PMC6042147, DOI: 10.1073/pnas.1806315115.Peer-Reviewed Original ResearchConceptsOrigin recognition complexRecognition complexAutoinhibited stateHeterohexameric origin recognition complexMetazoan origin recognition complexHuman origin recognition complexUnstructured N-terminal regionORC-DNA interactionDNA-binding channelMcm2-7 loadingNucleotide-dependent associationCryo-EM analysisDNA-binding mechanismN-terminal regionMinichromosome maintenance 2Replicative helicaseATPase domainAutoinhibited configurationContact DNAHelix foldCellular activitiesMaintenance 2Biochemical assaysDNACdc6
2017
Mechanisms for initiating cellular DNA replication
Bleichert F, Botchan MR, Berger JM. Mechanisms for initiating cellular DNA replication. Science 2017, 355 PMID: 28209641, DOI: 10.1126/science.aah6317.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsReplicative helicasesDNA replicationRing-shaped hexameric helicasesDNA replication factoriesDNA replication initiationDomains of lifeCellular DNA replicationDNA helixReplisome assemblyReplication initiationMolecular choreographyHexameric helicasesReplication factoriesAccessory proteinsHelicasesDNA synthesisMultistep processDNAHelixReplicationProteinMechanismInitiationAssemblyLoaderInterdomain Communication of the Chd1 Chromatin Remodeler across the DNA Gyres of the Nucleosome
Nodelman IM, Bleichert F, Patel A, Ren R, Horvath KC, Berger JM, Bowman GD. Interdomain Communication of the Chd1 Chromatin Remodeler across the DNA Gyres of the Nucleosome. Molecular Cell 2017, 65: 447-459.e6. PMID: 28111016, PMCID: PMC5308885, DOI: 10.1016/j.molcel.2016.12.011.Peer-Reviewed Original ResearchConceptsChromatin remodelersDNA gyresATPase motorChd1 chromatin remodelerDNA-binding domainDomain-domain communicationNucleosome assemblyNucleosome spacingNucleosomal DNAInterdomain communicationChd1 remodelerNucleosomesGenomic DNARemodelersDomain arrangementNucleosome coreDNAUnique organizationChromodomainDomain
2015
Crystal structure of the eukaryotic origin recognition complex
Bleichert F, Botchan MR, Berger JM. Crystal structure of the eukaryotic origin recognition complex. Nature 2015, 519: 321-326. PMID: 25762138, PMCID: PMC4368505, DOI: 10.1038/nature14239.Peer-Reviewed Original ResearchConceptsOrigin recognition complexDrosophila origin recognition complexRecognition complexEukaryotic origin recognition complexHeterohexameric origin recognition complexMini-chromosome maintenance 2Winged-helix domainCatalytic amino acidsCellular DNA replicationWinged-helix foldORC subunitsEncircles DNAHelicase loadingGenomic integrityORC functionDevelopmental controlDNA replicationÅ resolutionDomain interactionsDisrupts interactionsCell cycleMaintenance 2Amino acidsCentral channelUnanticipated features
2013
A Meier-Gorlin syndrome mutation in a conserved C-terminal helix of Orc6 impedes origin recognition complex formation
Bleichert F, Balasov M, Chesnokov I, Nogales E, Botchan MR, Berger JM. A Meier-Gorlin syndrome mutation in a conserved C-terminal helix of Orc6 impedes origin recognition complex formation. ELife 2013, 2: e00882. PMID: 24137536, PMCID: PMC3791464, DOI: 10.7554/elife.00882.Peer-Reviewed Original ResearchConceptsOrigin recognition complexMetazoan origin recognition complexMeier-Gorlin syndrome mutationsORC functionMcm2-7 loadingC-terminal helixMeier-Gorlin syndromeReplisome formationUncharacterized domainYeast complexRecognition complexDNA replicationEnigmatic functionSubunit organizationProper recruitmentBioinformatics analysisChromosomal originC-terminusOrc6Biochemical studiesCertain subunitsMutationsComplex formationSubunitsGlobal architecture
2009
A Dimeric Structure for Archaeal Box C/D Small Ribonucleoproteins
Bleichert F, Gagnon KT, Brown BA, Maxwell ES, Leschziner AE, Unger VM, Baserga SJ. A Dimeric Structure for Archaeal Box C/D Small Ribonucleoproteins. Science 2009, 325: 1384-1387. PMID: 19745151, PMCID: PMC2975540, DOI: 10.1126/science.1176099.Peer-Reviewed Original ResearchConceptsBox C/D sRNPArchaeal box C/D sRNPsRibosomal RNASingle-particle electron microscopyTarget ribosomal RNAArchaeon Methanocaldococcus jannaschiiOptimal protein synthesisRibose methylationMethanocaldococcus jannaschiiSmall ribonucleoproteinRNA componentEnzymatic functionSRNPDimeric structureMutational analysisProtein componentsProtein synthesisMethylationBase pairingRNAEukaryotesSnoRNPsArchaeaJannaschiiRibonucleoprotein