ArticleProceedings of the National Academy of Sciences of the United States of America2020
Structural mechanism of helicase loading onto replication origin DNA by ORC-Cdc6.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 68 citations in OpenAlex.
- DyProL: Dynamic Ensemble Representation Learning for Protein-Nucleic Acid Binding Site Prediction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- RNAs anchoring replication complex control initiation and firing of DNA replication.Nature communications · 2026Article
- Distinct roles of MCM2-7 subunits in replication licensing in human cells.Nature communications · 2026Article
- Assembly of a homohexameric minichromosome maintenance complex is dependent on ATP and DNA.The Journal of biological chemistry · 2026Article
- Archaeal and eukaryotic MCM rings sequentially melt DNA for replication initiation.Nature communications · 2026Article
- A Meier-Gorlin syndrome mutation impairs the loading of the MCM2-7 complex during DNA replication initiation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Dynamic DnaA-DnaB interactions at oriC coordinate the loading and coupled translocation of two DnaB helicases for bidirectional replication.Nucleic acids research · 2026Article
- A lethal ORC ATPase mutation is suppressed by alterations in ORC and RNA Pol II transcription components.PloS one · 2026Article
- Compact Origins and Where to Find Them: ORC's Guide to Genome-Wide Licensing.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Mechanisms for licensing origins of DNA replication in eukaryotic cells.Nature structural & molecular biology · 2025Review
- SEC-SAXS/MC Ensemble Structural Studies of the Microtubule Binding Protein Cdt1 Show Monomeric, Folded-Over Conformations.Cytoskeleton (Hoboken, N.J.) · 2025Article
- 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
- A high-throughput screening identifies MCM chromatin loading inhibitors targeting cells with increased replication origins.iScience · 2024Article
- Article
Corrections and comments
- Erratum issued
Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
DNA replication origins serve as sites of replicative helicase loading. In all eukaryotes, the six-subunit origin recognition complex (Orc1-6; ORC) recognizes the replication origin. During late M-phase of the cell-cycle, Cdc6 binds to ORC and the ORC-Cdc6 complex loads in a multistep reaction and, with the help of Cdt1, the core Mcm2-7 helicase onto DNA. A key intermediate is the ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) complex in which DNA has been already inserted into the central channel of Mcm2-7. Until now, it has been unclear how the origin DNA is guided by ORC-Cdc6 and inserted into the Mcm2-7 hexamer. Here, we truncated the C-terminal winged-helix-domain (WHD) of Mcm6 to slow down the loading reaction, thereby capturing two loading intermediates prior to DNA insertion in budding yeast. In "semi-attached OCCM," the Mcm3 and Mcm7 WHDs latch onto ORC-Cdc6 while the main body of the Mcm2-7 hexamer is not connected. In "pre-insertion OCCM," the main body of Mcm2-7 docks onto ORC-Cdc6, and the origin DNA is bent and positioned adjacent to the open DNA entry gate, poised for insertion, at the Mcm2-Mcm5 interface. We used molecular simulations to reveal the dynamic transition from preloading conformers to the loaded conformers in which the loading of Mcm2-7 on DNA is complete and the DNA entry gate is fully closed. Our work provides multiple molecular insights into a key event of eukaryotic DNA replication.
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