Natural Epigenetic DNA Modifications Cause Remote DNA Photodamage

5-Formyl-2'-deoxycytidine, an intermediate during the erasure of epigenetic marker 5-methyl-2'-deoxycytidine, and 5-formyl-2'-deoxyuridine, an oxidative lesion of thymidine, are naturally occurring DNA modifications. The carbonyl groups of these DNA modifications are the smallest possible photosensitizers and have the potential to generate cyclobutane pyrimidine dimers upon irradiation with UV light. To evidence this damaging potential, ternary DNA architectures were used, in which the photosensitizer and the damage site were located at well-defined positions in the sequences. The quantitative and time-dependent analysis revealed not only the high photodamaging potential of both natural DNA modifications but also the mechanisms for this new pathway to photodamage. 5-Formyl-2'-deoxycytidine is more efficiently generating cyclobutane pyrimidine dimers than 5-formyl-2'-deoxyuridine because the latter is also photochemically converted to 5-carboxy-2'-deoxyuridine. This demonstrates for the first time that epigenetic DNA modifications regulating gene expression interact with sunlight and can induce DNA photodamages.