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Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA

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  • Steven D. Bruner

    (Harvard University)

  • Derek P. G. Norman

    (Harvard University)

  • Gregory L. Verdine

    (Harvard University)

Abstract

Spontaneous oxidation of guanine residues in DNA generates 8-oxoguanine (oxoG). By mispairing with adenine during replication, oxoG gives rise to a G·C → T·A transversion, a frequent somatic mutation in human cancers. The dedicated repair pathway for oxoG centres on 8-oxoguanine DNA glycosylase (hOGG1), an enzyme that recognizes oxoG·C base pairs, catalysing expulsion of the oxoG and cleavage of the DNA backbone. Here we report the X-ray structure of the catalytic core of hOGG1 bound to oxoG·C-containing DNA at 2.1 Å resolution. The structure reveals the mechanistic basis for the recognition and catalytic excision of DNA damage by hOGG1 and by other members of the enzyme superfamily to which it belongs. The structure also provides a rationale for the biochemical effects of inactivating mutations and polymorphisms in hOGG1. One known mutation, R154H, converts hOGG1 to a pro-mutator by relaxing the specificity of the enzyme for the base opposite oxoG.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:403:y:2000:i:6772:d:10.1038_35002510
    DOI: 10.1038/35002510
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    Cited by:

    1. Tatu Pantsar & Sami Rissanen & Daniel Dauch & Tuomo Laitinen & Ilpo Vattulainen & Antti Poso, 2018. "Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling," PLOS Computational Biology, Public Library of Science, vol. 14(9), pages 1-23, September.
    2. Zhimin Tong & Huanxi Shen & Dandan Yang & Feng Zhang & Ying Bai & Qian Li & Jian Shi & Hengdong Zhang & Baoli Zhu, 2016. "Genetic Variations in the Promoter of the APE1 Gene Are Associated with DMF-Induced Abnormal Liver Function: A Case-Control Study in a Chinese Population," IJERPH, MDPI, vol. 13(8), pages 1-10, July.
    3. 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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