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Cryo-EM structure of a licensed DNA replication origin

Author

Listed:
  • Ferdos Abid Ali

    (The Francis Crick Institute)

  • Max E. Douglas

    (The Francis Crick Institute)

  • Julia Locke

    (The Francis Crick Institute)

  • Valerie E. Pye

    (The Francis Crick Institute)

  • Andrea Nans

    (The Francis Crick Institute)

  • John F. X. Diffley

    (The Francis Crick Institute)

  • Alessandro Costa

    (The Francis Crick Institute)

Abstract

Eukaryotic origins of replication are licensed upon loading of the MCM helicase motor onto DNA. ATP hydrolysis by MCM is required for loading and the post-catalytic MCM is an inactive double hexamer that encircles duplex DNA. Origin firing depends on MCM engagement of Cdc45 and GINS to form the CMG holo-helicase. CMG assembly requires several steps including MCM phosphorylation by DDK. To understand origin activation, here we have determined the cryo-EM structures of DNA-bound MCM, either unmodified or phosphorylated, and visualize a phospho-dependent MCM element likely important for Cdc45 recruitment. MCM pore loops touch both the Watson and Crick strands, constraining duplex DNA in a bent configuration. By comparing our new MCM–DNA structure with the structure of CMG–DNA, we suggest how the conformational transition from the loaded, post-catalytic MCM to CMG might promote DNA untwisting and melting at the onset of replication.

Suggested Citation

  • Ferdos Abid Ali & Max E. Douglas & Julia Locke & Valerie E. Pye & Andrea Nans & John F. X. Diffley & Alessandro Costa, 2017. "Cryo-EM structure of a licensed DNA replication origin," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02389-0
    DOI: 10.1038/s41467-017-02389-0
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    Cited by:

    1. Humberto Sánchez & Zhaowei Liu & Edo Veen & Theo Laar & John F. X. Diffley & Nynke H. Dekker, 2023. "A chromatinized origin reduces the mobility of ORC and MCM through interactions and spatial constraint," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Almutasem Saleh & Yasunori Noguchi & Ricardo Aramayo & Marina E. Ivanova & Kathryn M. Stevens & Alex Montoya & S. Sunidhi & Nicolas Lopez Carranza & Marcin J. Skwark & Christian Speck, 2022. "The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Daniel Ramírez Montero & Humberto Sánchez & Edo Veen & Theo Laar & Belén Solano & John F. X. Diffley & Nynke H. Dekker, 2023. "Nucleotide binding halts diffusion of the eukaryotic replicative helicase during activation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Hana Polasek-Sedlackova & Thomas C. R. Miller & Jana Krejci & Maj-Britt Rask & Jiri Lukas, 2022. "Solving the MCM paradox by visualizing the scaffold of CMG helicase at active replisomes," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Zaida Vergara & María S. Gomez & Bénédicte Desvoyes & Joana Sequeira-Mendes & Kinda Masoud & Celina Costas & Sandra Noir & Elena Caro & Victoria Mora-Gil & Pascal Genschik & Crisanto Gutierrez, 2023. "Distinct roles of Arabidopsis ORC1 proteins in DNA replication and heterochromatic H3K27me1 deposition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Jiaxuan Cheng & Ningning Li & Yunjing Huo & Shangyu Dang & Bik-Kwoon Tye & Ning Gao & Yuanliang Zhai, 2022. "Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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