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Time-lapse crystallography snapshots of a double-strand break repair polymerase in action

Author

Listed:
  • Joonas A. Jamsen

    (National Institutes of Health)

  • William A. Beard

    (National Institutes of Health)

  • Lars C. Pedersen

    (National Institutes of Health)

  • David D. Shock

    (National Institutes of Health)

  • Andrea F. Moon

    (National Institutes of Health)

  • Juno M. Krahn

    (National Institutes of Health)

  • Katarzyna Bebenek

    (National Institutes of Health)

  • Thomas A. Kunkel

    (National Institutes of Health)

  • Samuel H. Wilson

    (National Institutes of Health)

Abstract

DNA polymerase (pol) μ is a DNA-dependent polymerase that incorporates nucleotides during gap-filling synthesis in the non-homologous end-joining pathway of double-strand break repair. Here we report time-lapse X-ray crystallography snapshots of catalytic events during gap-filling DNA synthesis by pol μ. Unique catalytic intermediates and active site conformational changes that underlie catalysis are uncovered, and a transient third (product) metal ion is observed in the product state. The product manganese coordinates phosphate oxygens of the inserted nucleotide and PPi. The product metal is not observed during DNA synthesis in the presence of magnesium. Kinetic analyses indicate that manganese increases the rate constant for deoxynucleoside 5′-triphosphate insertion compared to magnesium. The likely product stabilization role of the manganese product metal in pol μ is discussed. These observations provide insight on structural attributes of this X-family double-strand break repair polymerase that impact its biological function in genome maintenance.

Suggested Citation

  • Joonas A. Jamsen & William A. Beard & Lars C. Pedersen & David D. Shock & Andrea F. Moon & Juno M. Krahn & Katarzyna Bebenek & Thomas A. Kunkel & Samuel H. Wilson, 2017. "Time-lapse crystallography snapshots of a double-strand break repair polymerase in action," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00271-7
    DOI: 10.1038/s41467-017-00271-7
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    Cited by:

    1. Joonas A. Jamsen & David D. Shock & Samuel H. Wilson, 2022. "Watching right and wrong nucleotide insertion captures hidden polymerase fidelity checkpoints," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Caleb Chang & Christie Lee Luo & Yang Gao, 2022. "In crystallo observation of three metal ion promoted DNA polymerase misincorporation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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