Molecular basis for proofreading by the unique exonuclease domain of Family-D DNA polymerases

Leonardo Betancurt-Anzola, Markel Martínez-Carranza, Marc Delarue, Kelly M. Zatopek (), Andrew F. Gardner () and Ludovic Sauguet ()
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Leonardo Betancurt-Anzola: Architecture and Dynamics of Biological Macromolecules, Institut Pasteur, Université Paris Cité, CNRS
Markel Martínez-Carranza: Architecture and Dynamics of Biological Macromolecules, Institut Pasteur, Université Paris Cité, CNRS
Marc Delarue: Architecture and Dynamics of Biological Macromolecules, Institut Pasteur, Université Paris Cité, CNRS
Kelly M. Zatopek: New England Biolabs Inc.
Andrew F. Gardner: New England Biolabs Inc.
Ludovic Sauguet: Architecture and Dynamics of Biological Macromolecules, Institut Pasteur, Université Paris Cité, CNRS

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Replicative DNA polymerases duplicate entire genomes at high fidelity. This feature is shared among the three domains of life and is facilitated by their dual polymerase and exonuclease activities. Family D replicative DNA polymerases (PolD), found exclusively in Archaea, contain an unusual RNA polymerase-like catalytic core, and a unique Mre11-like proofreading active site. Here, we present cryo-EM structures of PolD trapped in a proofreading mode, revealing an unanticipated correction mechanism that extends the repertoire of protein domains known to be involved in DNA proofreading. Based on our experimental structures, mutants of PolD were designed and their contribution to mismatch bypass and exonuclease kinetics was determined. This study sheds light on the convergent evolution of structurally distinct families of DNA polymerases, and the domain acquisition and exchange mechanism that occurred during the evolution of the replisome in the three domains of life.

Date: 2023
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DOI: 10.1038/s41467-023-44125-x

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