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Structural basis for human OGG1 processing 8-oxodGuo within nucleosome core particles

Author

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  • Mengtian Ren

    (Tiangong University
    Ludwig-Maximilians-Universität München
    Nankai University)

  • Fabian Gut

    (Ludwig-Maximilians-Universität München)

  • Yilan Fan

    (Ludwig-Maximilians-Universität München)

  • Jingke Ma

    (Nankai University)

  • Xiajing Shan

    (Nankai University)

  • Aysenur Yikilmazsoy

    (Ludwig-Maximilians-Universität München)

  • Mariia Likhodeeva

    (Ludwig-Maximilians-Universität München)

  • Karl-Peter Hopfner

    (Ludwig-Maximilians-Universität München)

  • Chuanzheng Zhou

    (Nankai University
    Nankai University)

Abstract

Base excision repair (BER) is initialized by DNA glycosylases, which recognize and flip damaged bases out of the DNA duplex into the enzymes active site, followed by cleavage of the glycosidic bond. Recent studies have revealed that all types of DNA glycosylases repair base lesions less efficiently within nucleosomes, and their repair activity is highly depended on the lesion’s location within the nucleosome. To reveal the underlying molecular mechanism of this phenomenon, we determine the 3.1 Å cryo-EM structure of human 8-oxoguanine-DNA glycosylase 1 (hOGG1) bound to a nucleosome core particle (NCP) containing a common oxidative base lesion, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo). Our structural analysis shows that hOGG1 can recognize and flip 8-oxodGuo even within NCPs; however, the interaction between 8-oxodGuo and hOGG1 in a NCP context is weaker than in free DNA due to competition for nucleosomal DNA by the histones. Binding of OGG1 and the flipping of 8-oxodGuo by hOGG1 leads to a partial detachment of DNA from the histone core and a ratchet-like inward movement of nucleosomal DNA. Our findings provide insights into how the dynamic structure of nucleosomes modulate the activity of repair enzymes within chromatin.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53811-3
    DOI: 10.1038/s41467-024-53811-3
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    References listed on IDEAS

    as
    1. Yan Qi & Marie C. Spong & Kwangho Nam & Anirban Banerjee & Sao Jiralerspong & Martin Karplus & Gregory L. Verdine, 2009. "Encounter and extrusion of an intrahelical lesion by a DNA repair enzyme," Nature, Nature, vol. 462(7274), pages 762-766, December.
    2. Anirban Banerjee & Wei Yang & Martin Karplus & Gregory L. Verdine, 2005. "Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA," Nature, Nature, vol. 434(7033), pages 612-618, March.
    3. 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.
    4. Steven D. Bruner & Derek P. G. Norman & Gregory L. Verdine, 2000. "Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA," Nature, Nature, vol. 403(6772), pages 859-866, February.
    5. Tyler M. Weaver & Nicole M. Hoitsma & Jonah J. Spencer & Lokesh Gakhar & Nicholas J. Schnicker & Bret D. Freudenthal, 2022. "Structural basis for APE1 processing DNA damage in the nucleosome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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