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Structure paper

TitleCell cycle regulation has shaped replication origins in budding yeast.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 9, Page 1697-1707, Year 2025
Publish dateJun 30, 2025
AuthorsChew Theng Lim / Thomas C R Miller / Kang Wei Tan / Saurabh Talele / Anne Early / Philip East / Humberto Sánchez / Nynke H Dekker / Alessandro Costa / John F X Diffley /
PubMed AbstractEukaryotic DNA replication initiates from 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 ...Eukaryotic DNA replication initiates from 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 by 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 the 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 MCM-ORC (MO) intermediate). CDK-dependent phosphorylation of this IDR blocks MO formation and DH assembly. We show that MO stabilizes ORC at 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. Strikingly, 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, strong 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.
External linksNat Struct Mol Biol / PubMed:40588661 / PubMed Central
MethodsEM (single particle)
Resolution2.79 - 4.4 Å
Structure data

19186

8rif

EMDB-19186, PDB-8rif:
Cryo-EM structure of the MCM double hexamer loaded onto dsDNA.
Method: EM (single particle) / Resolution: 2.79 Å

19187

8rig

EMDB-19187, PDB-8rig:
Cryo-EM structure of an MCM helicase single hexamer loaded onto dsDNA.
Method: EM (single particle) / Resolution: 3.41 Å

PDB-9i3i:
Cryo-EM structure of the MCM-ORC (MO) complex featuring an ORC2 regulatory domain involved in cell cycle regulation of MCM-DH loading for DNA replication.
Method: ELECTRON MICROSCOPY / Resolution: 4.4 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

Source
  • saccharomyces cerevisiae (brewer's yeast)
  • saccharomyces cerevisiae s288c (yeast)
KeywordsREPLICATION / MCM helicase / DNA replication / Origin licensing / MCM2-7 helicase / Origin Recognition Complex / CDK / cell cycle

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