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Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair

Author

Listed:
  • F. Li

    (Thomas Jefferson University
    University of Pennsylvania)

  • A. S. Phadte

    (Thomas Jefferson University)

  • M. Bhatia

    (Thomas Jefferson University)

  • S. Barndt

    (Thomas Jefferson University)

  • A. R. Monte Carlo III

    (Thomas Jefferson University)

  • C-F. D. Hou

    (Thomas Jefferson University
    Rutgers University)

  • R. Yang

    (Princeton University)

  • S. Strock

    (Thomas Jefferson University)

  • A. Pluciennik

    (Thomas Jefferson University)

Abstract

FAN1 is a DNA dependent nuclease whose proper function is essential for maintaining human health. For example, a genetic variant in FAN1, Arg507 to His hastens onset of Huntington’s disease, a repeat expansion disorder for which there is no cure. How the Arg507His mutation affects FAN1 structure and enzymatic function is unknown. Using cryo-EM and biochemistry, we have discovered that FAN1 arginine 507 is critical for its interaction with PCNA, and mutation of Arg507 to His attenuates assembly of the FAN1–PCNA complex on a disease-relevant extrahelical DNA extrusions formed within DNA repeats. This mutation concomitantly abolishes PCNA–FAN1–dependent cleavage of such extrusions, thus unraveling the molecular basis for a specific mutation in FAN1 that dramatically hastens the onset of Huntington’s disease. These results underscore the importance of PCNA to the genome stabilizing function of FAN1.

Suggested Citation

  • F. Li & A. S. Phadte & M. Bhatia & S. Barndt & A. R. Monte Carlo III & C-F. D. Hou & R. Yang & S. Strock & A. Pluciennik, 2025. "Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59323-y
    DOI: 10.1038/s41467-025-59323-y
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    References listed on IDEAS

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    1. Josh Abramson & Jonas Adler & Jack Dunger & Richard Evans & Tim Green & Alexander Pritzel & Olaf Ronneberger & Lindsay Willmore & Andrew J. Ballard & Joshua Bambrick & Sebastian W. Bodenstein & David , 2024. "Addendum: Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 636(8042), pages 4-4, December.
    2. Matteo De March & Nekane Merino & Susana Barrera-Vilarmau & Ramon Crehuet & Silvia Onesti & Francisco J. Blanco & Alfredo De Biasio, 2017. "Structural basis of human PCNA sliding on DNA," Nature Communications, Nature, vol. 8(1), pages 1-7, April.
    3. 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.
    4. Josh Abramson & Jonas Adler & Jack Dunger & Richard Evans & Tim Green & Alexander Pritzel & Olaf Ronneberger & Lindsay Willmore & Andrew J. Ballard & Joshua Bambrick & Sebastian W. Bodenstein & David , 2024. "Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 630(8016), pages 493-500, June.
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