Structural basis for DNA proofreading

Gina Buchel, Ashok R. Nayak, Karl Herbine, Azadeh Sarfallah, Viktoriia O. Sokolova, Angelica Zamudio-Ochoa and Dmitry Temiakov ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44198-8

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