2024
Multiple mechanisms for licensing human replication origins
Yang R, Hunker O, Wise M, Bleichert F. Multiple mechanisms for licensing human replication origins. Nature 2024, 1-11. PMID: 39604729, DOI: 10.1038/s41586-024-08237-8.Peer-Reviewed Original ResearchOrigin recognition complexReplication originsMCM loadingHexamer formationDNA replication initiationDNA replication machineryHuman replication originsOrc6 subunitMulticellular eukaryotesBiochemical reconstitutionReplication initiationRecognition complexReplicative helicaseMultiple mechanismsReplication machineryEukaryotic MCM2Helicase motorReplication stressOrigin licensingDimer interfaceOrc6Reconstituted systemYeastHexamerMCM2
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
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
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