Initiation of base excision repair: Glycosylase mechanisms and structures

The base excision repair pathway is an organism's primary defense against m utations induced by oxidative, alkylating, and other DNA-damaging agents. T his pathway is initiated by DNA glycosylases that excise the damaged base b y cleavage of the glycosidic bond between the base and the DNA sugar-phosph ate backbone. A subset of glycosylases has an associated apurinic/apyrimidi nic (AP) lyase activity that further processes the AP site to generate clea vage of the DNA phosphate backbone. Chemical mechanisms that are supported by biochemical and structural data have been proposed for several glycosyla ses and glycosylase/AP lyases. This review focuses on the chemical mechanis ms of catalysis in the context of recent structural information, with empha sis on the catalytic residues and the active site conformations of several cocrystal structures of glycosylases with their substrate DNAs. Common stru ctural motifs for DNA binding and damage specificity as well as conservatio n of acidic residues and amino groups for catalysis are discussed.