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A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6

Author

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  • Jan Marten Schmidt

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel
    Novartis Institutes for Biomedical Research)

  • Ran Yang

    (Yale University)

  • Ashish Kumar

    (Yale University)

  • Olivia Hunker

    (Yale University)

  • Jan Seebacher

    (Friedrich Miescher Institute for Biomedical Research)

  • Franziska Bleichert

    (Yale University)

Abstract

The coordinated action of multiple replicative helicase loading factors is needed for the licensing of replication origins prior to DNA replication. Binding of the Origin Recognition Complex (ORC) to DNA initiates the ATP-dependent recruitment of Cdc6, Cdt1 and Mcm2-7 loading, but the structural details for timely ATPase site regulation and for how loading can be impeded by inhibitory signals, such as cyclin-dependent kinase phosphorylation, are unknown. Using cryo-electron microscopy, we have determined several structures of S. cerevisiae ORC·DNA·Cdc6 intermediates at 2.5–2.7 Å resolution. These structures reveal distinct ring conformations of the initiator·co-loader assembly and inactive ATPase site configurations for ORC and Cdc6. The Orc6 N-terminal domain laterally engages the ORC·Cdc6 ring in a manner that is incompatible with productive Mcm2-7 docking, while deletion of this Orc6 region alleviates the CDK-mediated inhibition of Mcm7 recruitment. Our findings support a model in which Orc6 promotes the assembly of an autoinhibited ORC·DNA·Cdc6 intermediate to block origin licensing in response to CDK phosphorylation and to avert DNA re-replication.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28695-w
    DOI: 10.1038/s41467-022-28695-w
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    References listed on IDEAS

    as
    1. Jan Marten Schmidt & Franziska Bleichert, 2020. "Structural mechanism for replication origin binding and remodeling by a metazoan origin recognition complex and its co-loader Cdc6," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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    3. Ningning Li & Wai Hei Lam & Yuanliang Zhai & Jiaxuan Cheng & Erchao Cheng & Yongqian Zhao & Ning Gao & Bik-Kwoon Tye, 2018. "Structure of the origin recognition complex bound to DNA replication origin," Nature, Nature, vol. 559(7713), pages 217-222, July.
    4. Franziska Bleichert & Michael R. Botchan & James M. Berger, 2015. "Crystal structure of the eukaryotic origin recognition complex," Nature, Nature, vol. 519(7543), pages 321-326, March.
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    6. 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.
    7. Jordi Frigola & Dirk Remus & Amina Mehanna & John F. X. Diffley, 2013. "ATPase-dependent quality control of DNA replication origin licensing," Nature, Nature, vol. 495(7441), pages 339-343, March.
    8. Marina Guerrero-Puigdevall & Narcis Fernandez-Fuentes & Jordi Frigola, 2021. "Stabilisation of half MCM ring by Cdt1 during DNA insertion," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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