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The mechanism of DNA unwinding by the eukaryotic replicative helicase

Author

Listed:
  • Daniel R. Burnham

    (The Francis Crick Institute)

  • Hazal B. Kose

    (The Francis Crick Institute)

  • Rebecca B. Hoyle

    (University of Southampton)

  • Hasan Yardimci

    (The Francis Crick Institute)

Abstract

Accurate DNA replication is tightly regulated in eukaryotes to ensure genome stability during cell division and is performed by the multi-protein replisome. At the core an AAA+ hetero-hexameric complex, Mcm2-7, together with GINS and Cdc45 form the active replicative helicase Cdc45/Mcm2-7/GINS (CMG). It is not clear how this replicative ring helicase translocates on, and unwinds, DNA. We measure real-time dynamics of purified recombinant Drosophila melanogaster CMG unwinding DNA with single-molecule magnetic tweezers. Our data demonstrates that CMG exhibits a biased random walk, not the expected unidirectional motion. Through building a kinetic model we find CMG may enter up to three paused states rather than unwinding, and should these be prevented, in vivo fork rates would be recovered in vitro. We propose a mechanism in which CMG couples ATP hydrolysis to unwinding by acting as a lazy Brownian ratchet, thus providing quantitative understanding of the central process in eukaryotic DNA replication.

Suggested Citation

  • Daniel R. Burnham & Hazal B. Kose & Rebecca B. Hoyle & Hasan Yardimci, 2019. "The mechanism of DNA unwinding by the eukaryotic replicative helicase," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09896-2
    DOI: 10.1038/s41467-019-09896-2
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    Cited by:

    1. Zhichun Xu & Jianrong Feng & Daqi Yu & Yunjing Huo & Xiaohui Ma & Wai Hei Lam & Zheng Liu & Xiang David Li & Toyotaka Ishibashi & Shangyu Dang & Yuanliang Zhai, 2023. "Synergism between CMG helicase and leading strand DNA polymerase at replication fork," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. 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.
    3. Debashis Mondal & Manzoor Ahmad & Bijoy Dey & Abhishek Mondal & Pinaki Talukdar, 2022. "Formation of supramolecular channels by reversible unwinding-rewinding of bis(indole) double helix via ion coordination," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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