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The structure of ORC–Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6

Author

Listed:
  • Xiang Feng

    (Van Andel Institute)

  • Yasunori Noguchi

    (DNA Replication Group, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London
    MRC London Institute of Medical Sciences (LMS))

  • Marta Barbon

    (DNA Replication Group, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London
    MRC London Institute of Medical Sciences (LMS))

  • Bruce Stillman

    (Cold Spring Harbor Laboratory)

  • Christian Speck

    (DNA Replication Group, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London
    MRC London Institute of Medical Sciences (LMS))

  • Huilin Li

    (Van Andel Institute)

Abstract

The Origin Recognition Complex (ORC) binds to sites in chromosomes to specify the location of origins of DNA replication. The S. cerevisiae ORC binds to specific DNA sequences throughout the cell cycle but becomes active only when it binds to the replication initiator Cdc6. It has been unclear at the molecular level how Cdc6 activates ORC, converting it to an active recruiter of the Mcm2-7 hexamer, the core of the replicative helicase. Here we report the cryo-EM structure at 3.3 Å resolution of the yeast ORC–Cdc6 bound to an 85-bp ARS1 origin DNA. The structure reveals that Cdc6 contributes to origin DNA recognition via its winged helix domain (WHD) and its initiator-specific motif. Cdc6 binding rearranges a short α-helix in the Orc1 AAA+ domain and the Orc2 WHD, leading to the activation of the Cdc6 ATPase and the formation of the three sites for the recruitment of Mcm2-7, none of which are present in ORC alone. The results illuminate the molecular mechanism of a critical biochemical step in the licensing of eukaryotic replication origins.

Suggested Citation

  • Xiang Feng & Yasunori Noguchi & Marta Barbon & Bruce Stillman & Christian Speck & Huilin Li, 2021. "The structure of ORC–Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24199-1
    DOI: 10.1038/s41467-021-24199-1
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    Cited by:

    1. Jan Marten Schmidt & Ran Yang & Ashish Kumar & Olivia Hunker & Jan Seebacher & Franziska Bleichert, 2022. "A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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