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Watching right and wrong nucleotide insertion captures hidden polymerase fidelity checkpoints

Author

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  • Joonas A. Jamsen

    (National Institute of Environmental Health Sciences, National Institutes of Health)

  • David D. Shock

    (National Institute of Environmental Health Sciences, National Institutes of Health)

  • Samuel H. Wilson

    (National Institute of Environmental Health Sciences, National Institutes of Health)

Abstract

Efficient and accurate DNA synthesis is enabled by DNA polymerase fidelity checkpoints that promote insertion of the right instead of wrong nucleotide. Erroneous X-family polymerase (pol) λ nucleotide insertion leads to genomic instability in double strand break and base-excision repair. Here, time-lapse crystallography captures intermediate catalytic states of pol λ undergoing right and wrong natural nucleotide insertion. The revealed nucleotide sensing mechanism responds to base pair geometry through active site deformation to regulate global polymerase-substrate complex alignment in support of distinct optimal (right) or suboptimal (wrong) reaction pathways. An induced fit during wrong but not right insertion, and associated metal, substrate, side chain and pyrophosphate reaction dynamics modulated nucleotide insertion. A third active site metal hastened right but not wrong insertion and was not essential for DNA synthesis. The previously hidden fidelity checkpoints uncovered reveal fundamental strategies of polymerase DNA repair synthesis in genomic instability.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30141-w
    DOI: 10.1038/s41467-022-30141-w
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    References listed on IDEAS

    as
    1. Isaac J. Kimsey & Katja Petzold & Bharathwaj Sathyamoorthy & Zachary W. Stein & Hashim M. Al-Hashimi, 2015. "Visualizing transient Watson–Crick-like mispairs in DNA and RNA duplexes," Nature, Nature, vol. 519(7543), pages 315-320, March.
    2. Isaac J. Kimsey & Eric S. Szymanski & Walter J. Zahurancik & Anisha Shakya & Yi Xue & Chia-Chieh Chu & Bharathwaj Sathyamoorthy & Zucai Suo & Hashim M. Al-Hashimi, 2018. "Dynamic basis for dG•dT misincorporation via tautomerization and ionization," Nature, Nature, vol. 554(7691), pages 195-201, February.
    3. Bret D. Freudenthal & William A. Beard & Lalith Perera & David D. Shock & Taejin Kim & Tamar Schlick & Samuel H. Wilson, 2015. "Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide," Nature, Nature, vol. 517(7536), pages 635-639, January.
    4. 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.
    5. Alexey Rozov & Natalia Demeshkina & Eric Westhof & Marat Yusupov & Gulnara Yusupova, 2015. "Structural insights into the translational infidelity mechanism," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
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    Cited by:

    1. Karl Herbine & Ashok R. Nayak & Dmitry Temiakov, 2024. "Structural basis for substrate binding and selection by human mitochondrial RNA polymerase," Nature Communications, Nature, vol. 15(1), pages 1-9, December.

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