Related Experiment Video
Updated: Sep 17, 2025
08:40
Determination of S-Phase Duration Using 5-Ethynyl-2'-deoxyuridine Incorporation in Saccharomyces cerevisiae
Published on: October 21, 2022
1.6K
Cell cycle regulation has shaped replication origins in budding yeast.
Chew Theng Lim1, Thomas C R Miller2,3, Kang Wei Tan1
1Chromosome Replication Laboratory, The Francis Crick Institute, London, UK.
Nature Structural & Molecular Biology
|June 30, 2025
Summary
The origin recognition complex
Area of Science:
- Molecular Biology
- Cell Cycle Regulation
- DNA Replication
Background:
- Eukaryotic DNA replication initiates at origins, requiring MCM helicase loading.
- Origin Recognition Complex (ORC), Cdc6, and Cdt1 load MCM hexamers.
- Cyclin-Dependent Kinase (CDK) inhibits MCM loading to prevent re-replication.
Purpose of the Study:
- Investigate the role of Orc2's intrinsically disordered region (IDR) in MCM helicase loading.
- Elucidate the mechanism by which CDK inhibits MCM loading.
- Understand how certain origins escape cell cycle regulation.
Main Methods:
- Biochemical assays to study MCM-ORC (MO) intermediate formation.
- In vitro and in vivo experiments assessing helicase loading and CDK inhibition.
- Analysis of DNA replication origins with varying ORC binding site affinities.
Main Results:
- Orc2 IDR promotes interaction with the first MCM hexamer, forming the MO intermediate.
- CDK-mediated phosphorylation of Orc2 IDR inhibits MO formation and double hexamer (DH) assembly.
- MO stabilizes ORC at low-affinity sites for efficient second hexamer loading.
- Origins with high-affinity ORC sites bypass the MO-dependent pathway and escape CDK inhibition.
Conclusions:
- Mechanistic plasticity exists in MCM loading pathways.
- CDK regulation of MCM loading is adaptable and has influenced origin evolution.
- Understanding MCM loading provides insights into eukaryotic DNA replication and cell cycle control.
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