Theoretical study on the repair mechanism of the (6-4) photolesion by the (6-4) photolyase.
UV irradiation of DNA can lead to the formation of mutagenic (6-4) pyrimidine-pyrimidone photolesions. The (6-4) photolyases are the enzymes responsible for the photoinduced repair of such lesions. On the basis of the recently published crystal structure of the (6-4) photolyase bound to DNA [Maul et al. 2008] and employing quantum mechanics/molecular mechanics techniques, a repair mechanism is proposed, which involves two photoexcitations. The flavin chromophore, initially being in its reduced anionic form, is photoexcited and donates an electron to the (6-4) form of the photolesion. The photolesion is then protonated by the neighboring histidine residue and forms a radical intermediate. The latter undergoes a series of energy stabilizing hydrogen-bonding rearrangements before the electron back transfer to the flavin semiquinone. The resulting structure corresponds to the oxetane intermediate, long thought to be formed upon DNA-enzyme binding. A second photoexcitation of the flavin promotes another electron transfer to the oxetane. Proton donation from the same histidine residue allows for the splitting of the four-membered ring, hence opening an efficient pathway to the final repaired form. The repair of the lesion by a single photoexcitation was shown not to be feasible.
Sadeghian
Keyarash
K
Institute of Physical and Theoretical Chemistry, University of Regensburg, Universitätsstraβe 31, D-93040 Regensburg, Germany.
Bocola
Marco
M
Merz
Thomas
T
Schütz
Martin
M
D000818:Animals; D018360:Crystallography, X-Ray; D004247:DNA / Q000235:genetics / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair; D004255:Deoxyribodipyrimidine Photo-Lyase / Q000737:chemistry*; D004331:Drosophila melanogaster / Q000201:enzymology; D011522:Protons; D011740:Pyrimidine Dimers / Q000737:chemistry*; D011789:Quantum Theory; D011995:Recombination, Genetic; D014466:Ultraviolet Rays; D014867:Water / Q000737:chemistry
D011522:Protons; D011740:Pyrimidine Dimers; C058406:pyrimidine-pyrimidone dimer; D014867:Water; D004247:DNA; C098727:pyrimidine(6-4)pyrimidone photolyase; D004255:Deoxyribodipyrimidine Photo-Lyase