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Structure of DNA-CMG-Pol epsilon elucidates the roles of the non-catalytic polymerase modules in the eukaryotic replisome

Author

Listed:
  • Panchali Goswami

    (The Francis Crick Institute)

  • Ferdos Abid Ali

    (The Francis Crick Institute)

  • Max E. Douglas

    (The Francis Crick Institute)

  • Julia Locke

    (The Francis Crick Institute)

  • Andrew Purkiss

    (The Francis Crick Institute)

  • Agnieszka Janska

    (The Francis Crick Institute)

  • Patrik Eickhoff

    (The Francis Crick Institute)

  • Anne Early

    (The Francis Crick Institute)

  • Andrea Nans

    (The Francis Crick Institute)

  • Alan M. C. Cheung

    (University College London
    Birkbeck College)

  • John F. X. Diffley

    (The Francis Crick Institute)

  • Alessandro Costa

    (The Francis Crick Institute)

Abstract

Eukaryotic origin firing depends on assembly of the Cdc45-MCM-GINS (CMG) helicase. A key step is the recruitment of GINS that requires the leading-strand polymerase Pol epsilon, composed of Pol2, Dpb2, Dpb3, Dpb4. While a truncation of the catalytic N-terminal Pol2 supports cell division, Dpb2 and C-terminal Pol2 (C-Pol2) are essential for viability. Dpb2 and C-Pol2 are non-catalytic modules, shown or predicted to be related to an exonuclease and DNA polymerase, respectively. Here, we present the cryo-EM structure of the isolated C-Pol2/Dpb2 heterodimer, revealing that C-Pol2 contains a DNA polymerase fold. We also present the structure of CMG/C-Pol2/Dpb2 on a DNA fork, and find that polymerase binding changes both the helicase structure and fork-junction engagement. Inter-subunit contacts that keep the helicase-polymerase complex together explain several cellular phenotypes. At least some of these contacts are preserved during Pol epsilon-dependent CMG assembly on path to origin firing, as observed with DNA replication reconstituted in vitro.

Suggested Citation

  • Panchali Goswami & Ferdos Abid Ali & Max E. Douglas & Julia Locke & Andrew Purkiss & Agnieszka Janska & Patrik Eickhoff & Anne Early & Andrea Nans & Alan M. C. Cheung & John F. X. Diffley & Alessandro, 2018. "Structure of DNA-CMG-Pol epsilon elucidates the roles of the non-catalytic polymerase modules in the eukaryotic replisome," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07417-1
    DOI: 10.1038/s41467-018-07417-1
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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. Leonardo Betancurt-Anzola & Markel Martínez-Carranza & Marc Delarue & Kelly M. Zatopek & Andrew F. Gardner & Ludovic Sauguet, 2023. "Molecular basis for proofreading by the unique exonuclease domain of Family-D DNA polymerases," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Qing He & Feng Wang & Nina Y. Yao & Michael E. O’Donnell & Huilin Li, 2024. "Structures of the human leading strand Polε–PCNA holoenzyme," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Matthew Day & Bilal Tetik & Milena Parlak & Yasser Almeida-Hernández & Markus Räschle & Farnusch Kaschani & Heike Siegert & Anika Marko & Elsa Sanchez-Garcia & Markus Kaiser & Isabel A. Barker & Laure, 2024. "TopBP1 utilises a bipartite GINS binding mode to support genome replication," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Sameera Vipat & Dipika Gupta & Sagun Jonchhe & Hele Anderspuk & Eli Rothenberg & Tatiana N. Moiseeva, 2022. "The non-catalytic role of DNA polymerase epsilon in replication initiation in human cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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