DNA photocleavage by triplex forming oligonucleotides (TFO) has potential implications in both biotechnology and medicine. We have synthesized a series of homopurine DNA and DNA/LNA 14-mers to which an amino acid (glycine or l-tryptophan) and a cyanine dye are covalently linked. Two cyanine dyes were examined that include a quinolinium ring linked to a benzothiazolium ring through a monomethine (TO1) or trimethine (TO2) linker. The 14-mer sequence was chosen to target mdm2, a ubiquitin ligase (E3) that regulates p53 by promoting its ubiquitylation and proteosomal degradation. Such inhibition has been previously proposed as a therapeutic approach to target wild-type p53-expressing cancers. To examine whether our TFO conjugates photocleave the mdm2 target, we incubated the various conjugates with the mdm2 plasmid and irradiated the samples with visible light. We show that only the TFO with the complementary sequence and with an intervening l-tryptophan leads to the linearization of the plasmid after a short irradiation time (10 min) exciting the dye (λmax(TO1) = 500 nm and λmax(TO2) = 630 nm) with visible light. Furthermore, the photoreactivity is more pronounced for the LNA/DNA conjugate, an observation that is consistent with improved hybridization to the DNA target. Sequence specificity of the photoreaction is further corroborated on a synthetic 44-mer duplex containing the TFO site. Evidence for a ROS-dependent mechanism is also given and discussed.