Structural basis for the lack of opposite base specificity of Clostridium acetobutylicum 8-oxoguanine DNA glycosylase |
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| Authors: | Frédérick Faucher Susan S Wallace Sylvie Doublié |
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| Institution: | 1. Departments of Medicine and Molecular Microbiology and the Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110;3. From the Laboratory of Molecular Gerontology,;4. Laboratory of Molecular Biology and Immunology, NIA, National Institutes of Health, Baltimore, Maryland 21224,;5. National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031 China,;6. Department of Medicine, Institute for Research in Immunology and Cancer, University of Montréal, Montréal, Québec H3C 3J7, Canada;3. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138;5. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138;4. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138;6. Graduate Program in Biophysics, Harvard Medical School, Boston, Massachusetts 02115 |
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| Abstract: | 7,8-Dihydro-8-oxoguanine (8-oxoG) is the major oxidative product of guanine and the most prevalent base lesion observed in DNA molecules. Because 8-oxoG has the capability to form a Hoogsteen pair with adenine (8-oxoG:A) in addition to a normal Watson–Crick pair with cytosine (8-oxoG:C), this lesion can lead to a G:C → T:A transversion after replication. However, 8-oxoG is recognized and excised by the 8-oxoguanine DNA glycosylase (Ogg) of the base excision repair pathway. Members of the Ogg1 family usually display a strong preference for a C opposite the lesion. In contrast, the atypical Ogg1 from Clostridium actetobutylicum (CacOgg) can excise 8-oxoG when paired with either one of the four bases, albeit with a preference for C and A. Here we describe the first high-resolution crystal structures of CacOgg in complex with duplex DNA containing the 8-oxoG lesion paired to cytosine and to adenine. A structural comparison with human OGG1 provides a rationale for the lack of opposite base specificity displayed by the bacterial Ogg. |
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