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Cell Cycle Regulation has Shaped Budding Yeast Replication Origin Structure and Function
Open accessPreprint — published as 10.1038/s41594-025-01591-9
Abstract
Summary: Eukaryotic DNA replication initiates from multiple genomic loci known as origins. At budding yeast origins like ARS1, a double hexamer (DH) of the MCM replicative helicase is assembled by Origin Recognition Complex (ORC), Cdc6 and Cdt1 via sequential hexamer loading from two opposed ORC binding sites. Cyclin Dependent Kinase (CDK) inhibits DH assembly, which prevents re-replication by restricting helicase loading to G1 phase. Here we show that an intrinsically disordered region (IDR) in the Orc2 subunit promotes interaction between ORC and the first loaded, closed-ring MCM hexamer (the MO intermediate); CDK phosphorylation of this IDR blocks MO formation and DH assembly. We show that MO functions by stabilising ORC at the lower affinity binding sites required for second hexamer loading. Origins comprising two high affinity ORC sites can assemble DH efficiently without MO by independently loading single hexamers; these origins escape CDK inhibition in vitro and in vivo . Our work reveals mechanistic plasticity in MCM loading with implications for understanding how CDK regulation has shaped yeast origin evolution and how natural origins might escape cell cycle regulation. We also identify key steps common to loading pathways, with implications for understanding how MCM is loaded in other eukaryotes.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Lim, C. T., Miller, T. C. R., Tan, K. W., Talele, S., Early, A., East, P., Sánchez, H., Dekker, N. H., Costa, A., & Diffley, J. F. X.
- Affiliations
- The Francis Crick Institute (GB)
- University of Copenhagen (DK)
- University of Oxford (GB)
- Delft University of Technology (NL)
- Corresponding author
- Miller, Thomas C.R.
- Diffley, John F.X.
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Publisher
- openRxiv
- Published
- 2024-01-10
- Volume
- 32
- Issue
- 9
- Pages
- 1697-1707
- ISSN
- 1545-9985 (ISSN-L)
- PMC
- PMC12440816
- OpenAlex
- W4411830097
- Cited by
- 11
- References
- 1
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Funders
- Wellcome Trust (106252/Z/14/Z, 219527/Z/19/Z, 820102, CC2002, FC001066, FC001065, CC2009)
- Francis Crick Institute (FC001065, FC001066)
- Cancer Research UK (820102, FC001065, FC001066)
- European Commission (HORIZON2020)
- National Research Foundation (DNRF115)
- Danmarks Grundforskningsfond (DNRF115])
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (OCENW.M.21.173)
- Novo Nordisk
- Novo Nordisk Fonden
- Medical Research Council (820102, FC001065, FC001066)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- origin of replication, MCM helicase, CDK phosphorylation, origin recognition complex, cell cycle regulation, Saccharomyces cerevisiae, ARS1, re-replication
- MeSH terms
- Binding Sites, Cell Cycle, DNA Replication, Saccharomycetales, Phosphorylation, Saccharomyces cerevisiae, Replication Origin, Cell Cycle Proteins, Cyclin-Dependent Kinases, Saccharomyces cerevisiae Proteins, Origin Recognition Complex, Minichromosome Maintenance Proteins
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