Charge separation is one of the most common consequences of the absorption of UV light by DNA. Recently, it has been shown that this process can enable efficient self-repair of cyclobutane pyrimidine dimers (CPDs) in specific short DNA oligomers such as the GAT[double bond, length as m-dash]T sequence. The mechanism was characterized as sequential electron transfer through the nucleobase stack which is controlled by the redox potentials of nucleobases and their sequence. Here, we demonstrate that the inverse sequence T[double bond, length as m-dash]TAG promotes self-repair with higher quantum yields (0.58 ± 0.23%) than GAT[double bond, length as m-dash]T (0.44 ± 0.18%) in a comparative study involving UV-irradiation experiments. After extended exposure to UV irradiation, a photostationary equilibrium between self-repair and damage formation is reached at 33 ± 13% for GAT[double bond, length as m-dash]T and at 40 ± 16% for T[double bond, length as m-dash]TAG, which corresponds to the maximum total yield of self-repair. Molecular dynamics and quantum mechanics/molecular mechanics (QM/MM) simulations allowed us to assign this disparity to better stacking overlap between the G and A bases, which lowers the energies of the key A-˙G+˙ charge transfer state in the dominant conformers of the T[double bond, length as m-dash]TAG tetramer. These conformational differences also hinder alternative photorelaxation pathways of the T[double bond, length as m-dash]TAG tetranucleotide, which otherwise compete with the sequential electron transfer mechanism responsible for CPD self-repair. Overall, we demonstrate that photoinduced electron transfer is strongly dependent on conformation and the availability of alternative photodeactivation mechanisms. This knowledge can be used in the identification and prediction of canonical and modified DNA sequences exhibiting efficient electron transfer. It also further contributes to our understanding of DNA self-repair and its potential role in the photochemical selection of the most photostable sequences on the early Earth.

Department of Astronomy Harvard Smithsonian Center for Astrophysics 60 Garden Street Cambridge MA 02138 USA

Department of Chemistry and Chemical Biology Harvard University Cambridge Massachusetts 02138 USA

Department of Chemistry The University of Chicago Chicago Illinois 60637 USA

Department of Earth and Planetary Sciences Harvard University Cambridge Massachusetts 02138 USA

Howard Hughes Medical Institute Department of Molecular Biology and Center for Computational and Integrative Biology Massachusetts General Hospital Boston Massachusetts 02114 USA

Howard Hughes Medical Institute The University of Chicago Chicago IL 60637 USA

Institute of Advanced Materials Faculty of Chemistry Wrocław University of Science and Technology Wybrzeże Wyspiańskiego 27 Wrocław 50 370 Poland

Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 61200 Brno Czech Republic

Regional Centre of Advanced Technologies and Materials Czech Advanced Technology and Research Institute Palacky University Olomouc Slechtitelu 241 27 783 71 Olomouc Holice Czech Republic

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