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Zusammenfassung:
Mutagenic pyrimidine-pyrimidone (6−4) photoproducts are one of the main DNA lesions induced by solar UV radiation. These lesions can be photoreversed by (6−4) photolyases. The originally published repair mechanism involves rearrangement of the lesion into an oxetane intermediate upon binding to the (6−4) photolyase, followed by light-induced electron transfer from the reduced flavin cofactor. In a recent crystallographic study on a (6−4) photoproduct complexed with (6-4) photolyase from Drosophila melanogaster no oxetane was observed, raising the possibility of a non-oxetane repair mechanism. Using quantum-chemical calculations we find that in addition to repair via an oxetane, a direct transfer of the hydroxyl group results in reversal of the radical anion (6−4) photoproduct. In both mechanisms, the transition states have high energies and correspond to avoided crossings of the ground and excited electronic states. To study whether the repair can proceed via these state crossings, the excited-state potential energy curves were computed. The radical excitation energies and accessibility of the nonadiabatic repair path were found to depend on hydrogen bonds and the protonation state of the lesion. On the basis of the energy calculations, a nonadiabatic repair of the excited (6−4) lesion radical anion via hydroxyl transfer is probable. This repair mechanism is in line with the recent structural data on the (6−4) photolyase from D. melanogaster.
