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Structural basis for DNA proofreading

Author

Listed:
  • Gina Buchel

    (Thomas Jefferson University)

  • Ashok R. Nayak

    (Thomas Jefferson University)

  • Karl Herbine

    (Thomas Jefferson University)

  • Azadeh Sarfallah

    (Thomas Jefferson University)

  • Viktoriia O. Sokolova

    (Thomas Jefferson University)

  • Angelica Zamudio-Ochoa

    (Thomas Jefferson University)

  • Dmitry Temiakov

    (Thomas Jefferson University)

Abstract

DNA polymerase (DNAP) can correct errors in DNA during replication by proofreading, a process critical for cell viability. However, the mechanism by which an erroneously incorporated base translocates from the polymerase to the exonuclease site and the corrected DNA terminus returns has remained elusive. Here, we present an ensemble of nine high-resolution structures representing human mitochondrial DNA polymerase Gamma, Polγ, captured during consecutive proofreading steps. The structures reveal key events, including mismatched base recognition, its dissociation from the polymerase site, forward translocation of DNAP, alterations in DNA trajectory, repositioning and refolding of elements for primer separation, DNAP backtracking, and displacement of the mismatched base into the exonuclease site. Altogether, our findings suggest a conserved ‘bolt-action’ mechanism of proofreading based on iterative cycles of DNAP translocation without dissociation from the DNA, facilitating primer transfer between catalytic sites. Functional assays and mutagenesis corroborate this mechanism, connecting pathogenic mutations to crucial structural elements in proofreading steps.

Suggested Citation

  • Gina Buchel & Ashok R. Nayak & Karl Herbine & Azadeh Sarfallah & Viktoriia O. Sokolova & Angelica Zamudio-Ochoa & Dmitry Temiakov, 2023. "Structural basis for DNA proofreading," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44198-8
    DOI: 10.1038/s41467-023-44198-8
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    References listed on IDEAS

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    1. Aleksandra Trifunovic & Anna Wredenberg & Maria Falkenberg & Johannes N. Spelbrink & Anja T. Rovio & Carl E. Bruder & Mohammad Bohlooly-Y & Sebastian Gidlöf & Anders Oldfors & Rolf Wibom & Jan Törnell, 2004. "Premature ageing in mice expressing defective mitochondrial DNA polymerase," Nature, Nature, vol. 429(6990), pages 417-423, May.
    2. Ana Bratic & Timo E. S. Kauppila & Bertil Macao & Sebastian Grönke & Triinu Siibak & James B. Stewart & Francesca Baggio & Jacqueline Dols & Linda Partridge & Maria Falkenberg & Anna Wredenberg & Nils, 2015. "Complementation between polymerase- and exonuclease-deficient mitochondrial DNA polymerase mutants in genomically engineered flies," Nature Communications, Nature, vol. 6(1), pages 1-15, December.
    3. Sylvie Doublié & Stanley Tabor & Alexander M. Long & Charles C. Richardson & Tom Ellenberger, 1998. "Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 Å resolution," Nature, Nature, vol. 391(6664), pages 251-258, January.
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