Article
Nature 452, 961-965 (24 April 2008) | doi:10.1038/nature06889; Received 17 December 2007; Accepted 5 March 2008
Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA
Cai-Guang Yang1,3, Chengqi Yi1,3, Erica M. Duguid1, Christopher T. Sullivan1, Xing Jian1, Phoebe A. Rice2 & Chuan He1
- Department of Chemistry, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA
- Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA
- These authors contributed equally to this work.
Correspondence to: Chuan He1 Correspondence and requests for materials should be addressed to C.H. (Email: chuanhe@uchicago.edu).
Abstract
Escherichia coli AlkB and its human homologues ABH2 and ABH3 repair DNA/RNA base lesions by using a direct oxidative dealkylation mechanism. ABH2 has the primary role of guarding mammalian genomes against 1-meA damage by repairing this lesion in double-stranded DNA (dsDNA), whereas AlkB and ABH3 preferentially repair single-stranded DNA (ssDNA) lesions and can repair damaged bases in RNA. Here we show the first crystal structures of AlkB–dsDNA and ABH2–dsDNA complexes, stabilized by a chemical cross-linking strategy. This study reveals that AlkB uses an unprecedented base-flipping mechanism to access the damaged base: it squeezes together the two bases flanking the flipped-out one to maintain the base stack, explaining the preference of AlkB for repairing ssDNA lesions over dsDNA ones. In addition, the first crystal structure of ABH2, presented here, provides a structural basis for designing inhibitors of this human DNA repair protein.