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Encounter and extrusion of an intrahelical lesion by a DNA repair enzyme

Author

Listed:
  • Yan Qi

    (Graduate Program in Biophysics, Harvard Medical School, Boston, Massachusetts 02115)

  • Marie C. Spong

    (Chemistry and Chemical Biology,)

  • Kwangho Nam

    (Chemistry and Chemical Biology,)

  • Anirban Banerjee

    (Chemistry and Chemical Biology,
    Present addresses: Rockefeller University, New York, New York 10021, USA (A.B.); Department of Biochemistry and Molecular Biology, Division of Cancer Medicine, University of Texas, MD Anderson Centre, Houston, Texas 77030, USA (S.J.).)

  • Sao Jiralerspong

    (Chemistry and Chemical Biology,
    Present addresses: Rockefeller University, New York, New York 10021, USA (A.B.); Department of Biochemistry and Molecular Biology, Division of Cancer Medicine, University of Texas, MD Anderson Centre, Houston, Texas 77030, USA (S.J.).)

  • Martin Karplus

    (Chemistry and Chemical Biology,
    Institut de Science et d’Ingénierie Supramoléculaires (ISIS), Université de Strasbourg, 8 allée Gasparol Monge, 67000 Strasbourg, France)

  • Gregory L. Verdine

    (Graduate Program in Biophysics, Harvard Medical School, Boston, Massachusetts 02115
    Chemistry and Chemical Biology,
    Molecular and Cellular Biology, and,
    Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA)

Abstract

How living systems detect the presence of genotoxic damage embedded in a million-fold excess of undamaged DNA is an unresolved question in biology. Here we have captured and structurally elucidated a base-excision DNA repair enzyme, MutM, at the stage of initial encounter with a damaged nucleobase, 8-oxoguanine (oxoG), nested within a DNA duplex. Three structures of intrahelical oxoG-encounter complexes are compared with sequence-matched structures containing a normal G base in place of an oxoG lesion. Although the protein–DNA interfaces in the matched complexes differ by only two atoms—those that distinguish oxoG from G—their pronounced structural differences indicate that MutM can detect a lesion in DNA even at the earliest stages of encounter. All-atom computer simulations show the pathway by which encounter of the enzyme with the lesion causes extrusion from the DNA duplex, and they elucidate the critical free energy difference between oxoG and G along the extrusion pathway.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:462:y:2009:i:7274:d:10.1038_nature08561
    DOI: 10.1038/nature08561
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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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