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Mechanism of human Lig1 regulation by PCNA in Okazaki fragment sealing

Author

Listed:
  • Kerry Blair

    (University of Leicester)

  • Muhammad Tehseen

    (King Abdullah University of Science and Technology)

  • Vlad-Stefan Raducanu

    (King Abdullah University of Science and Technology)

  • Taha Shahid

    (University of Leicester
    King Abdullah University of Science and Technology)

  • Claudia Lancey

    (University of Leicester)

  • Fahad Rashid

    (King Abdullah University of Science and Technology)

  • Ramon Crehuet

    (CSIC-Institute for Advanced Chemistry of Catalonia (IQAC) C/ Jordi Girona 18-26)

  • Samir M. Hamdan

    (King Abdullah University of Science and Technology)

  • Alfredo De Biasio

    (University of Leicester
    King Abdullah University of Science and Technology)

Abstract

During lagging strand synthesis, DNA Ligase 1 (Lig1) cooperates with the sliding clamp PCNA to seal the nicks between Okazaki fragments generated by Pol δ and Flap endonuclease 1 (FEN1). We present several cryo-EM structures combined with functional assays, showing that human Lig1 recruits PCNA to nicked DNA using two PCNA-interacting motifs (PIPs) located at its disordered N-terminus (PIPN-term) and DNA binding domain (PIPDBD). Once Lig1 and PCNA assemble as two-stack rings encircling DNA, PIPN-term is released from PCNA and only PIPDBD is required for ligation to facilitate the substrate handoff from FEN1. Consistently, we observed that PCNA forms a defined complex with FEN1 and nicked DNA, and it recruits Lig1 to an unoccupied monomer creating a toolbelt that drives the transfer of DNA to Lig1. Collectively, our results provide a structural model on how PCNA regulates FEN1 and Lig1 during Okazaki fragments maturation.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35475-z
    DOI: 10.1038/s41467-022-35475-z
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    References listed on IDEAS

    as
    1. 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.
    2. John M. Pascal & Patrick J. O'Brien & Alan E. Tomkinson & Tom Ellenberger, 2004. "Human DNA ligase I completely encircles and partially unwinds nicked DNA," Nature, Nature, vol. 432(7016), pages 473-478, November.
    3. Fahad Rashid & Vlad-Stefan Raducanu & Manal S. Zaher & Muhammad Tehseen & Satoshi Habuchi & Samir M. Hamdan, 2019. "Initial state of DNA-Dye complex sets the stage for protein induced fluorescence modulation," Nature Communications, Nature, vol. 10(1), pages 1-14, 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. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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    1. Javier Zamarreño & Sofía Muñoz & Esmeralda Alonso-Rodríguez & Macarena Alcalá & Sergio Rodríguez & Rodrigo Bermejo & María P. Sacristán & Avelino Bueno, 2024. "Timely lagging strand maturation relies on Ubp10 deubiquitylase-mediated PCNA dissociation from replicating chromatin," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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