ArticleProceedings of the National Academy of Sciences of the United States of America2023
Changing protein-DNA interactions promote ORC binding-site exchange during replication origin licensing.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 14 citations in OpenAlex.
- Distinct roles of MCM2-7 subunits in replication licensing in human cells.Nature communications · 2026Article
- A lethal ORC ATPase mutation is suppressed by alterations in ORC and RNA Pol II transcription components.PloS one · 2026Article
- An Orc6 tether mediates ORC binding-site switching during replication origin licensing.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cell cycle regulation has shaped replication origins in budding yeast.Nature structural & molecular biology · 2025Article
- Mechanisms for licensing origins of DNA replication in eukaryotic cells.Nature structural & molecular biology · 2025Review
- DNA bending mediated by ORC is essential for replication licensing in budding yeast.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- How similar are the molecular mechanisms of yeast and metazoan genome replication initiation?Biochemical Society transactions · 2025Review
- Unidirectional MCM translocation away from ORC drives origin licensing.Nature communications · 2025Article
- Reconstitution of human DNA licensing and the structural and functional analysis of key intermediates.Nature communications · 2025Article
- MCM2-7 ring closure involves the Mcm5 C-terminus and triggers Mcm4 ATP hydrolysis.Nature communications · 2025Article
- Article
- MCM2-7 loading-dependent ORC release ensures genome-wide origin licensing.Nature communications · 2024Article
- Multiple pathways for licensing human replication origins.bioRxiv : the preprint server for biology · 2024Article
- Changing protein-DNA interactions promote ORC binding-site exchange during replication origin licensing.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
During origin licensing, the eukaryotic replicative helicase Mcm2-7 forms head-to-head double hexamers to prime origins for bidirectional replication. Recent single-molecule and structural studies revealed that one molecule of the helicase loader ORC (origin recognition complex) can sequentially load two Mcm2-7 hexamers to ensure proper head-to-head helicase alignment. To perform this task, ORC must release from its initial high-affinity DNA-binding site and "flip" to bind a weaker, inverted DNA site. However, the mechanism of this binding-site switch remains unclear. In this study, we used single-molecule Förster resonance energy transfer to study the changing interactions between DNA and ORC or Mcm2-7. We found that the loss of DNA bending that occurs during DNA deposition into the Mcm2-7 central channel increases the rate of ORC dissociation from DNA. Further studies revealed temporally controlled DNA sliding of helicase-loading intermediates and that the first sliding complex includes ORC, Mcm2-7, and Cdt1. We demonstrate that sequential events of DNA unbending, Cdc6 release, and sliding lead to a stepwise decrease in ORC stability on DNA, facilitating ORC dissociation from its strong binding site during site switching. In addition, the controlled sliding we observed provides insight into how ORC accesses secondary DNA-binding sites at different locations relative to the initial binding site. Our study highlights the importance of dynamic protein-DNA interactions in the loading of two oppositely oriented Mcm2-7 helicases to ensure bidirectional DNA replication.
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