STRUCTURAL BASIS FOR THE EXCISION-REPAIR OF ALKYLATION-DAMAGED DNA

Base-excision DNA repair proteins that target alkylation damage act on a variety of seemingly dissimilar adducts, yet fail to recognize othe r closely related lesions. The 1.8 Angstrom crystal structure of the m onofunctional DNA glycosylase AlkA (E. coli 9-methyladenine-DNA glycos ylase II) reveals a large hydrophobic cleft unusually rich in aromatic residues. An Asp residue projecting into this cleft is essential for catalysis, and it governs binding specificity for mechanism-based inhi bitors. We propose that AlkA recognizes electron-deficient methylated bases through pi-donor/acceptor interactions involving the electron-ri ch aromatic cleft. Remarkably, AlkA is similar in fold and active site location to the bifunctional glycosylase/lyase endonuclease III, sugg esting the two may employ fundamentally related mechanisms for base ex cision.