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DNA unwinding mechanism of a eukaryotic replicative CMG helicase

Author

Listed:
  • Zuanning Yuan

    (Van Andel Institute)

  • Roxana Georgescu

    (Howard Hughes Medical Institute
    The Rockefeller University)

  • Lin Bai

    (Van Andel Institute)

  • Dan Zhang

    (The Rockefeller University)

  • Huilin Li

    (Van Andel Institute)

  • Michael E. O’Donnell

    (Howard Hughes Medical Institute
    The Rockefeller University)

Abstract

High-resolution structures have not been reported for replicative helicases at a replication fork at atomic resolution, a prerequisite to understanding the unwinding mechanism. The eukaryotic replicative CMG (Cdc45, Mcm2-7, GINS) helicase contains a Mcm2-7 motor ring, with the N-tier ring in front and the C-tier motor ring behind. The N-tier ring is structurally divided into a zinc finger (ZF) sub-ring followed by the oligosaccharide/oligonucleotide-binding (OB) fold ring. Here we report the cryo-EM structure of CMG on forked DNA at 3.9 Å, revealing that parental DNA enters the ZF sub-ring and strand separation occurs at the bottom of the ZF sub-ring, where the lagging strand is blocked and diverted sideways by OB hairpin-loops of Mcm3, Mcm4, Mcm6, and Mcm7. Thus, instead of employing a specific steric exclusion process, or even a separation pin, unwinding is achieved via a “dam-and-diversion tunnel” mechanism that does not require specific protein-DNA interaction. The C-tier motor ring contains spirally configured PS1 and H2I loops of Mcms 2, 3, 5, 6 that translocate on the spirally-configured leading strand, and thereby pull the preceding DNA segment through the diversion tunnel for strand separation.

Suggested Citation

  • Zuanning Yuan & Roxana Georgescu & Lin Bai & Dan Zhang & Huilin Li & Michael E. O’Donnell, 2020. "DNA unwinding mechanism of a eukaryotic replicative CMG helicase," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14577-6
    DOI: 10.1038/s41467-020-14577-6
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    Cited by:

    1. 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.
    2. Fritz Nagae & Yasuto Murayama & Tsuyoshi Terakawa, 2024. "Molecular mechanism of parental H3/H4 recycling at a replication fork," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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