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The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase

Author

Listed:
  • Uddhav K. Shigdel

    (Harvard University
    Harvard University
    LifeMine Therapeutics)

  • Victor Ovchinnikov

    (Harvard University)

  • Seung-Joo Lee

    (Harvard University
    Beam Therapeutics)

  • Jenny A. Shih

    (Harvard University
    Beth Israel Deaconess Medical Center)

  • Martin Karplus

    (Harvard University
    Université de Strasbourg)

  • Kwangho Nam

    (University of Texas at Arlington
    Umeå University)

  • Gregory L. Verdine

    (Harvard University
    Harvard University)

Abstract

Efficient search for DNA damage embedded in vast expanses of the DNA genome presents one of the greatest challenges to DNA repair enzymes. We report here crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, that interact with the DNA containing the damaged base oxoG and the normal base G while they are nested in the DNA helical stack. The structures reveal that hOGG1 engages the DNA using different protein-DNA contacts from those observed in the previously determined lesion recognition complex and other hOGG1-DNA complexes. By applying molecular dynamics simulations, we have determined the pathways taken by the lesion and normal bases when extruded from the DNA helix and their associated free energy profiles. These results reveal how the human oxoG DNA glycosylase hOGG1 locates the lesions inside the DNA helix and facilitates their extrusion for repair.

Suggested Citation

  • Uddhav K. Shigdel & Victor Ovchinnikov & Seung-Joo Lee & Jenny A. Shih & Martin Karplus & Kwangho Nam & Gregory L. Verdine, 2020. "The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18290-2
    DOI: 10.1038/s41467-020-18290-2
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    Cited by:

    1. Mengtian Ren & Fabian Gut & Yilan Fan & Jingke Ma & Xiajing Shan & Aysenur Yikilmazsoy & Mariia Likhodeeva & Karl-Peter Hopfner & Chuanzheng Zhou, 2024. "Structural basis for human OGG1 processing 8-oxodGuo within nucleosome core particles," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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