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Structure of the processive human Pol δ holoenzyme

Author

Listed:
  • Claudia Lancey

    (University of Leicester)

  • Muhammad Tehseen

    (King Abdullah University of Science and Technology)

  • Vlad-Stefan Raducanu

    (King Abdullah University of Science and Technology)

  • Fahad Rashid

    (King Abdullah University of Science and Technology)

  • Nekane Merino

    (CIC bioGUNE, Parque Tecnológico de Bizkaia Edificio 800)

  • Timothy J. Ragan

    (University of Leicester)

  • Christos G. Savva

    (University of Leicester)

  • Manal S. Zaher

    (King Abdullah University of Science and Technology)

  • Afnan Shirbini

    (King Abdullah University of Science and Technology)

  • Francisco J. Blanco

    (CIC bioGUNE, Parque Tecnológico de Bizkaia Edificio 800
    IKERBASQUE, Basque Foundation for Science)

  • Samir M. Hamdan

    (King Abdullah University of Science and Technology)

  • Alfredo De Biasio

    (University of Leicester)

Abstract

In eukaryotes, DNA polymerase δ (Pol δ) bound to the proliferating cell nuclear antigen (PCNA) replicates the lagging strand and cooperates with flap endonuclease 1 (FEN1) to process the Okazaki fragments for their ligation. We present the high-resolution cryo-EM structure of the human processive Pol δ–DNA–PCNA complex in the absence and presence of FEN1. Pol δ is anchored to one of the three PCNA monomers through the C-terminal domain of the catalytic subunit. The catalytic core sits on top of PCNA in an open configuration while the regulatory subunits project laterally. This arrangement allows PCNA to thread and stabilize the DNA exiting the catalytic cleft and recruit FEN1 to one unoccupied monomer in a toolbelt fashion. Alternative holoenzyme conformations reveal important functional interactions that maintain PCNA orientation during synthesis. This work sheds light on the structural basis of Pol δ’s activity in replicating the human genome.

Suggested Citation

  • Claudia Lancey & Muhammad Tehseen & Vlad-Stefan Raducanu & Fahad Rashid & Nekane Merino & Timothy J. Ragan & Christos G. Savva & Manal S. Zaher & Afnan Shirbini & Francisco J. Blanco & Samir M. Hamdan, 2020. "Structure of the processive human Pol δ holoenzyme," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14898-6
    DOI: 10.1038/s41467-020-14898-6
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    Cited by:

    1. André Bortolini Silveira & Alexandre Houy & Olivier Ganier & Begüm Özemek & Sandra Vanhuele & Anne Vincent-Salomon & Nathalie Cassoux & Pascale Mariani & Gaelle Pierron & Serge Leyvraz & Damian Rieke , 2024. "Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Kerry Blair & Muhammad Tehseen & Vlad-Stefan Raducanu & Taha Shahid & Claudia Lancey & Fahad Rashid & Ramon Crehuet & Samir M. Hamdan & Alfredo De Biasio, 2022. "Mechanism of human Lig1 regulation by PCNA in Okazaki fragment sealing," Nature Communications, Nature, vol. 13(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. Vlad-Stefan Raducanu & Muhammad Tehseen & Amani Al-Amodi & Luay I. Joudeh & Alfredo Biasio & Samir M. Hamdan, 2022. "Mechanistic investigation of human maturation of Okazaki fragments reveals slow kinetics," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Claudia Lancey & Muhammad Tehseen & Souvika Bakshi & Matthew Percival & Masateru Takahashi & Mohamed A. Sobhy & Vlad S. Raducanu & Kerry Blair & Frederick W. Muskett & Timothy J. Ragan & Ramon Crehuet, 2021. "Cryo-EM structure of human Pol κ bound to DNA and mono-ubiquitylated PCNA," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    6. Yejinpeng Wang & Lingao Ju & Gang Wang & Kaiyu Qian & Wan Jin & Mingxing Li & Jingtian Yu & Yiliang Shi & Yongzhi Wang & Yi Zhang & Yu Xiao & Xinghuan Wang, 2023. "DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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