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Article: Multiple pathways for licensing human replication origins.

Yang, Ran / Hunker, Olivia / Wise, Marleigh / Bleichert, Franziska

bioRxiv : the preprint server for biology

2024

Abstract: The loading of replicative helicases constitutes an obligatory step in the assembly of DNA replication machineries. In eukaryotes, the MCM2-7 replicative helicase motor is deposited onto DNA by the origin recognition complex (ORC) and co-loader proteins ... ...

Abstract	The loading of replicative helicases constitutes an obligatory step in the assembly of DNA replication machineries. In eukaryotes, the MCM2-7 replicative helicase motor is deposited onto DNA by the origin recognition complex (ORC) and co-loader proteins as a head-to-head MCM double hexamer to license replication origins. Although extensively studied in the budding yeast model system, the mechanisms of origin licensing in higher eukaryotes remain poorly defined. Here, we use biochemical reconstitution and electron microscopy (EM) to reconstruct the human MCM loading pathway. Unexpectedly, we find that, unlike in yeast, ORC's Orc6 subunit is not essential for human MCM loading but can enhance loading efficiency. EM analyses identify several intermediates
Language	English
Publishing date	2024-04-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.10.588796
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Article ; Online: Mechanisms of replication origin licensing: a structural perspective.

Bleichert, Franziska

Current opinion in structural biology

2019 Volume 59, Page(s) 195–204

Abstract: The duplication of chromosomal DNA is a key cell cycle event that involves the controlled, bidirectional assembly of the replicative machinery. In a tightly regulated, multi-step reaction, replicative helicases and other components of the DNA synthesis ... ...

Abstract	The duplication of chromosomal DNA is a key cell cycle event that involves the controlled, bidirectional assembly of the replicative machinery. In a tightly regulated, multi-step reaction, replicative helicases and other components of the DNA synthesis apparatus are recruited to replication start sites. Although the molecular approaches for assembling this machinery vary between the different domains of life, a common theme revolves around the use of ATP-dependent initiation factors to recognize and remodel origins and to load replicative helicases in a bidirectional manner onto DNA. This review summarizes recent advances in understanding the mechanisms of replication initiation in eukaryotes, focusing on how the replicative helicase is loaded in this system.
MeSH term(s)	Adenosine Triphosphate/chemistry ; Adenosine Triphosphate/metabolism ; DNA/chemistry ; DNA/genetics ; DNA/ultrastructure ; DNA Helicases/chemistry ; DNA Helicases/metabolism ; DNA Replication ; DNA-Directed DNA Polymerase/chemistry ; DNA-Directed DNA Polymerase/metabolism ; Hydrolysis ; Models, Molecular ; Multienzyme Complexes/chemistry ; Multienzyme Complexes/metabolism ; Protein Binding ; Quantitative Structure-Activity Relationship ; Replication Origin
Chemical Substances	Multienzyme Complexes ; Adenosine Triphosphate (8L70Q75FXE) ; DNA (9007-49-2) ; DNA synthesome (EC 2.7.7.-) ; DNA-Directed DNA Polymerase (EC 2.7.7.7) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2019-10-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2019.08.007
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Article ; Online: A dual role for the chromatin reader ORCA/LRWD1 in targeting the origin recognition complex to chromatin.

Sahu, Sumon / Ekundayo, Babatunde E / Kumar, Ashish / Bleichert, Franziska

The EMBO journal

2023 Volume 42, Issue 18, Page(s) e114654

Abstract: Eukaryotic cells use chromatin marks to regulate the initiation of DNA replication. The origin recognition complex (ORC)-associated protein ORCA plays a critical role in heterochromatin replication in mammalian cells by recruiting the initiator ORC, but ... ...

Abstract	Eukaryotic cells use chromatin marks to regulate the initiation of DNA replication. The origin recognition complex (ORC)-associated protein ORCA plays a critical role in heterochromatin replication in mammalian cells by recruiting the initiator ORC, but the underlying mechanisms remain unclear. Here, we report crystal and cryo-electron microscopy structures of ORCA in complex with ORC's Orc2 subunit and nucleosomes, establishing that ORCA orchestrates ternary complex assembly by simultaneously recognizing a highly conserved peptide sequence in Orc2, nucleosomal DNA, and repressive histone trimethylation marks through an aromatic cage. Unexpectedly, binding of ORCA to nucleosomes prevents chromatin array compaction in a manner that relies on H4K20 trimethylation, a histone modification critical for heterochromatin replication. We further show that ORCA is necessary and sufficient to specifically recruit ORC into chromatin condensates marked by H4K20 trimethylation, providing a paradigm for studying replication initiation in specific chromatin contexts. Collectively, our findings support a model in which ORCA not only serves as a platform for ORC recruitment to nucleosomes bearing specific histone marks but also helps establish a local chromatin environment conducive to subsequent MCM2-7 loading.
MeSH term(s)	Animals ; Chromatin/genetics ; Heterochromatin/genetics ; Origin Recognition Complex/genetics ; Origin Recognition Complex/metabolism ; Nucleosomes/genetics ; Cryoelectron Microscopy ; DNA Replication ; Transcription Factors/genetics ; Replication Origin ; Mammals/genetics
Chemical Substances	Chromatin ; Heterochromatin ; Origin Recognition Complex ; Nucleosomes ; Transcription Factors
Language	English
Publishing date	2023-08-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2023114654
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Article ; Online: Structural mechanism for replication origin binding and remodeling by a metazoan origin recognition complex and its co-loader Cdc6.

Schmidt, Jan Marten / Bleichert, Franziska

Nature communications

2020 Volume 11, Issue 1, Page(s) 4263

Abstract: Eukaryotic DNA replication initiation relies on the origin recognition complex (ORC), a DNA-binding ATPase that loads the Mcm2-7 replicative helicase onto replication origins. Here, we report cryo-electron microscopy (cryo-EM) structures of DNA-bound ... ...

Abstract	Eukaryotic DNA replication initiation relies on the origin recognition complex (ORC), a DNA-binding ATPase that loads the Mcm2-7 replicative helicase onto replication origins. Here, we report cryo-electron microscopy (cryo-EM) structures of DNA-bound Drosophila ORC with and without the co-loader Cdc6. These structures reveal that Orc1 and Orc4 constitute the primary DNA binding site in the ORC ring and cooperate with the winged-helix domains to stabilize DNA bending. A loop region near the catalytic Walker B motif of Orc1 directly contacts DNA, allosterically coupling DNA binding to ORC's ATPase site. Correlating structural and biochemical data show that DNA sequence modulates DNA binding and remodeling by ORC, and that DNA bending promotes Mcm2-7 loading in vitro. Together, these findings explain the distinct DNA sequence-dependencies of metazoan and S. cerevisiae initiators in origin recognition and support a model in which DNA geometry and bendability contribute to Mcm2-7 loading site selection in metazoans.
MeSH term(s)	AAA Domain ; Adenosine Triphosphate/metabolism ; Animals ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cryoelectron Microscopy ; DNA/chemistry ; DNA/metabolism ; Drosophila Proteins/chemistry ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Hydrolysis ; Minichromosome Maintenance Proteins/chemistry ; Minichromosome Maintenance Proteins/genetics ; Minichromosome Maintenance Proteins/metabolism ; Models, Molecular ; Origin Recognition Complex/chemistry ; Origin Recognition Complex/genetics ; Origin Recognition Complex/metabolism ; Protein Binding ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Replication Origin/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	Cdc6 protein, Drosophila ; Cell Cycle Proteins ; Drosophila Proteins ; Origin Recognition Complex ; Recombinant Proteins ; Saccharomyces cerevisiae Proteins ; Adenosine Triphosphate (8L70Q75FXE) ; DNA (9007-49-2) ; Minichromosome Maintenance Proteins (EC 3.6.4.12)
Language	English
Publishing date	2020-08-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-18067-7
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Article ; Online: Origins of DNA replication.

Ekundayo, Babatunde / Bleichert, Franziska

PLoS genetics

2019 Volume 15, Issue 9, Page(s) e1008320

Abstract: In all kingdoms of life, DNA is used to encode hereditary information. Propagation of the genetic material between generations requires timely and accurate duplication of DNA by semiconservative replication prior to cell division to ensure each daughter ... ...

Abstract	In all kingdoms of life, DNA is used to encode hereditary information. Propagation of the genetic material between generations requires timely and accurate duplication of DNA by semiconservative replication prior to cell division to ensure each daughter cell receives the full complement of chromosomes. DNA synthesis of daughter strands starts at discrete sites, termed replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, organisms have evolved surprisingly divergent strategies that control replication onset. Here, we discuss commonalities and differences in replication origin organization and recognition in the three domains of life.
MeSH term(s)	Biological Evolution ; Cell Division/genetics ; Chromosomes/genetics ; DNA Replication/genetics ; DNA Replication/physiology ; Evolution, Molecular ; Replication Origin/genetics ; Replicon/genetics
Language	English
Publishing date	2019-09-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1008320
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Article ; Online: Structural mechanism for replication origin binding and remodeling by a metazoan origin recognition complex and its co-loader Cdc6

Jan Marten Schmidt / Franziska Bleichert

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 17

Abstract: The origin recognition complex (ORC) is essential for loading the Mcm2–7 replicative helicase onto DNA during DNA replication initiation. Here, the authors describe several cryo-electron microscopy structures of Drosophila ORC bound to DNA and its ... ...

Abstract	The origin recognition complex (ORC) is essential for loading the Mcm2–7 replicative helicase onto DNA during DNA replication initiation. Here, the authors describe several cryo-electron microscopy structures of Drosophila ORC bound to DNA and its cofactor Cdc6 and also report an in vitro reconstitution system for Drosophila Mcm2–7 loading, revealing unexpected features of ORC’s DNA binding and remodeling mechanism during Mcm2–7 loading.
Keywords	Science ; Q
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural mechanism for replication origin binding and remodeling by a metazoan origin recognition complex and its co-loader Cdc6

Jan Marten Schmidt / Franziska Bleichert

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 17

Abstract	The origin recognition complex (ORC) is essential for loading the Mcm2–7 replicative helicase onto DNA during DNA replication initiation. Here, the authors describe several cryo-electron microscopy structures of Drosophila ORC bound to DNA and its cofactor Cdc6 and also report an in vitro reconstitution system for Drosophila Mcm2–7 loading, revealing unexpected features of ORC’s DNA binding and remodeling mechanism during Mcm2–7 loading.
Keywords	Science ; Q
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
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Article ; Online: A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6.

Schmidt, Jan Marten / Yang, Ran / Kumar, Ashish / Hunker, Olivia / Seebacher, Jan / Bleichert, Franziska

Nature communications

2022 Volume 13, Issue 1, Page(s) 1059

Abstract: The coordinated action of multiple replicative helicase loading factors is needed for the licensing of replication origins prior to DNA replication. Binding of the Origin Recognition Complex (ORC) to DNA initiates the ATP-dependent recruitment of Cdc6, ... ...

Abstract	The coordinated action of multiple replicative helicase loading factors is needed for the licensing of replication origins prior to DNA replication. Binding of the Origin Recognition Complex (ORC) to DNA initiates the ATP-dependent recruitment of Cdc6, Cdt1 and Mcm2-7 loading, but the structural details for timely ATPase site regulation and for how loading can be impeded by inhibitory signals, such as cyclin-dependent kinase phosphorylation, are unknown. Using cryo-electron microscopy, we have determined several structures of S. cerevisiae ORC·DNA·Cdc6 intermediates at 2.5-2.7 Å resolution. These structures reveal distinct ring conformations of the initiator·co-loader assembly and inactive ATPase site configurations for ORC and Cdc6. The Orc6 N-terminal domain laterally engages the ORC·Cdc6 ring in a manner that is incompatible with productive Mcm2-7 docking, while deletion of this Orc6 region alleviates the CDK-mediated inhibition of Mcm7 recruitment. Our findings support a model in which Orc6 promotes the assembly of an autoinhibited ORC·DNA·Cdc6 intermediate to block origin licensing in response to CDK phosphorylation and to avert DNA re-replication.
MeSH term(s)	Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cryoelectron Microscopy ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; DNA/metabolism ; DNA Helicases/metabolism ; DNA Replication ; Minichromosome Maintenance Complex Component 7/genetics ; Origin Recognition Complex/metabolism ; Protein Binding ; Replication Origin ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	CDC6 protein, S cerevisiae ; Cell Cycle Proteins ; Origin Recognition Complex ; Saccharomyces cerevisiae Proteins ; DNA (9007-49-2) ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; DNA Helicases (EC 3.6.4.-) ; MCM7 protein, S cerevisiae (EC 3.6.4.12) ; Minichromosome Maintenance Complex Component 7 (EC 3.6.4.12)
Language	English
Publishing date	2022-02-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-28695-w
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Article ; Online: A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6

Jan Marten Schmidt / Ran Yang / Ashish Kumar / Olivia Hunker / Jan Seebacher / Franziska Bleichert

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 13

Abstract: Cryo-EM structures of S. cerevisiae ORC bound to DNA and Cdc6 reveal an autoinhibited conformation and suggest a mechanism of origin licensing control in response to CDK phosphorylation. ...

Abstract	Cryo-EM structures of S. cerevisiae ORC bound to DNA and Cdc6 reveal an autoinhibited conformation and suggest a mechanism of origin licensing control in response to CDK phosphorylation.
Keywords	Science ; Q
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mechanisms for initiating cellular DNA replication.

Bleichert, Franziska / Botchan, Michael R / Berger, James M

Science (New York, N.Y.)

2017 Volume 355, Issue 6327

Abstract: Cellular DNA replication factories depend on ring-shaped hexameric helicases to aid DNA synthesis by processively unzipping the parental DNA helix. Replicative helicases are loaded onto DNA by dedicated initiator, loader, and accessory proteins during ... ...

Abstract	Cellular DNA replication factories depend on ring-shaped hexameric helicases to aid DNA synthesis by processively unzipping the parental DNA helix. Replicative helicases are loaded onto DNA by dedicated initiator, loader, and accessory proteins during the initiation of DNA replication in a tightly regulated, multistep process. We discuss here the molecular choreography of DNA replication initiation across the three domains of life, highlighting similarities and differences in the strategies used to deposit replicative helicases onto DNA and to melt the DNA helix in preparation for replisome assembly. Although initiators and loaders are phylogenetically related, the mechanisms they use for accomplishing similar tasks have diverged considerably and in an unpredictable manner.
MeSH term(s)	Archaea/enzymology ; Archaea/genetics ; Archaea/metabolism ; Bacteria/enzymology ; Bacteria/genetics ; Bacteria/metabolism ; Cells/enzymology ; Cells/metabolism ; DNA Helicases/chemistry ; DNA Helicases/metabolism ; DNA Replication ; Eukaryota/enzymology ; Eukaryota/genetics ; Eukaryota/metabolism ; Helix-Turn-Helix Motifs ; Phylogeny ; Protein Domains
Chemical Substances	DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2017-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aah6317
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Zs.MG 77: Show issues

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