Crystal Structure and Mechanism of a DNA (6-4) Photolyase

Angew. Chem. Int. Ed., 2008, 47, 10.1002/anie.200804268 published on 27.10.2008
Angewandte Chemie Int. Ed., online article
UV irradiation of cells gives rise to the formation of cyclobutane pyrimidine dimers (CPD) and so-called (6-4) DNA lesions (Scheme 1). Both lesions are major photoproducts formed in dipyrimidine sequences of double-stranded DNA. Repair of these lesions is essential because of their high mutagenic potential. Particularly important in many organisms are the photolyase-mediated repair systems that are able to split CPD lesions and (6-4) lesions directly back into their corresponding monomers. While formation and photolyase repair of CPD lesions is well studied, little is known about (6-4) lesions. In particular, the mechanism of repair of the (6-4) lesions by (6-4) DNAphotolyases is a longstanding question. Currently it is believed that the enzyme rearranges the (6-4) lesion with the help of two conserved histidine residues in the active site to form an oxetane intermediate (Scheme 1), which is split after single-electron donation from a light-activated FADH. We report here the first crystal structures of a (6-4) DNA photolyase enzyme. The structures show the enzyme in complex with a (6-4) lesion containing DNAbefore and after in situ repair. Based on the structural and biochemical data we propose a modified repair mechanism that lacks the strained oxetane intermediate.

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