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Article
Nature Structural Biology  10, 204 - 211 (2003)
Published online: 18 February 2003; | doi:10.1038/nsb902

Product-assisted catalysis in base-excision DNA repair

J. Christopher Fromme1, Steven D. Bruner2, 3, Wei Yang2, Martin Karplus2 & Gregory L. Verdine1, 2

1  Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

2  Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

3  Present address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Correspondence should be addressed to Gregory L. Verdine verdine@chemistry.harvard.edu
Most spontaneous damage to bases in DNA is corrected through the action of the base-excision DNA repair pathway. Base excision repair is initiated by DNA glycosylases, lesion-specific enzymes that intercept aberrant bases in DNA and catalyze their excision. How such proteins accomplish the feat of catalyzing no fewer than five sequential reaction steps using a single active site has been unknown. To help answer this, we report the structure of a trapped catalytic intermediate in DNA repair by human 8-oxoguanine DNA glycosylase. This structure and supporting biochemical results reveal that the enzyme sequesters the excised lesion base and exploits it as a cofactor to participate in catalysis. To our knowledge, the present example represents the first documented case of product-assisted catalysis in an enzyme-catalyzed reaction.

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Nature Structural & Molecular Biology
ISSN: 1545-9993
EISSN: 1545-9985
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