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ATPase-dependent quality control of DNA replication origin licensing

Author

Listed:
  • Jordi Frigola

    (Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK)

  • Dirk Remus

    (Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK
    Present address: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.)

  • Amina Mehanna

    (Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK)

  • John F. X. Diffley

    (Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK)

Abstract

The regulated loading of the Mcm2–7 DNA helicase (comprising six related subunits, Mcm2 to Mcm7) into pre-replicative complexes at multiple replication origins ensures precise once per cell cycle replication in eukaryotic cells. The origin recognition complex (ORC), Cdc6 and Cdt1 load Mcm2–7 into a double hexamer bound around duplex DNA in an ATP-dependent reaction, but the molecular mechanism of this origin ‘licensing’ is still poorly understood. Here we show that both Mcm2–7 hexamers in Saccharomyces cerevisiae are recruited to origins by an essential, conserved carboxy-terminal domain of Mcm3 that interacts with and stimulates the ATPase activity of ORC–Cdc6. ATP hydrolysis can promote Mcm2–7 loading, but can also promote Mcm2–7 release if components are missing or if ORC has been inactivated by cyclin-dependent kinase phosphorylation. Our work provides new insights into how origins are licensed and reveals a novel ATPase-dependent mechanism contributing to precise once per cell cycle replication.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:495:y:2013:i:7441:d:10.1038_nature11920
    DOI: 10.1038/nature11920
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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. 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.
    3. Yue Wu & Qiongdan Zhang & Yuhan Lin & Wai Hei Lam & Yuanliang Zhai, 2024. "Replication licensing regulated by a short linear motif within an intrinsically disordered region of origin recognition complex," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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