ArticleProceedings of the National Academy of Sciences of the United States of America2023
Regulation of replication origin licensing by ORC phosphorylation reveals a two-step mechanism for Mcm2-7 ring closing.
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 15 papers.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
- MCM2 germline variants predispose to familial papillary thyroid carcinoma due to genomic instability caused by MCM complex disruption.Oncogene · 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
- 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
- MCM2-7 ring closure involves the Mcm5 C-terminus and triggers Mcm4 ATP hydrolysis.Nature communications · 2025Article
- Article
- Replication licensing regulated by a short linear motif within an intrinsically disordered region of origin recognition complex.Nature communications · 2024Article
- Multiple pathways for licensing human replication origins.bioRxiv : the preprint server for biology · 2024Article
- The Origin Recognition Complex: From Origin Selection to Replication Licensing in Yeast and Humans.Biology · 2023Review
- 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
- Regulation of replication origin licensing by ORC phosphorylation reveals a two-step mechanism for Mcm2-7 ring closing.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Changing protein-DNA interactions promote ORC binding site exchange during replication origin licensing.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Eukaryotic DNA replication must occur exactly once per cell cycle to maintain cell ploidy. This outcome is ensured by temporally separating replicative helicase loading (G1 phase) and activation (S phase). In budding yeast, helicase loading is prevented outside of G1 by cyclin-dependent kinase (CDK) phosphorylation of three helicase-loading proteins: Cdc6, the Mcm2-7 helicase, and the origin recognition complex (ORC). CDK inhibition of Cdc6 and Mcm2-7 is well understood. Here we use single-molecule assays for multiple events during origin licensing to determine how CDK phosphorylation of ORC suppresses helicase loading. We find that phosphorylated ORC recruits a first Mcm2-7 to origins but prevents second Mcm2-7 recruitment. The phosphorylation of the Orc6, but not of the Orc2 subunit, increases the fraction of first Mcm2-7 recruitment events that are unsuccessful due to the rapid and simultaneous release of the helicase and its associated Cdt1 helicase-loading protein. Real-time monitoring of first Mcm2-7 ring closing reveals that either Orc2 or Orc6 phosphorylation prevents Mcm2-7 from stably encircling origin DNA. Consequently, we assessed formation of the MO complex, an intermediate that requires the closed-ring form of Mcm2-7. We found that ORC phosphorylation fully inhibits MO complex formation and we provide evidence that this event is required for stable closing of the first Mcm2-7. Our studies show that multiple steps of helicase loading are impacted by ORC phosphorylation and reveal that closing of the first Mcm2-7 ring is a two-step process started by Cdt1 release and completed by MO complex formation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.