Oxidative Damage Generated by an Oxo-Metalloporphyrin onto the Human Telomeric Sequence

Abstract

The cationic metalloporphyrin Mn-TMPyP activated by KHSO(5) has been used as cleaver of an oligonucleotide containing the four human telomere repeats of 5'-GGGTTA. This oligonucleotide formed an intramolecular quadruplex DNA under 200 mM KCl as probed by DMS footprinting and could fold into different quadruplex structures under 200 mM NaCl. We found that the oxo-metalloporphyrin was able to mediate efficient oxidative cleavage of the quadruplex. The location of damage showed that the metalloporphyrin was able to bind to the last G-tetrad of the quadruplex structure via an external interaction. This metalloporphyrin-G-tetrad interaction needs a relatively high flexibility of the single-stranded linker regions to allow the partial stacking of the metalloporphyrin with the last G-tetrad planar structure. The oxidative damage consisted of guanine oxidation within the interacting G-tetrad together with an 1'-carbon hydroxylation of deoxyribose residues of the thymidine residues located on the neighboring single-stranded loop. So the high-valent oxo-metalloporphyrin is able to mediate both electron-abstraction or H-abstraction on G or T residues, respectively, within the DNA quadruplex target.

Porphyrin Derivatives for Telomere Binding and Telomerase Inhibition

“…However, this compound is able to interact with quadruplex DNA since it is very efficient in the degradation of quadruplex DNA of the human telomeric sequence. [32] The damage was shown to take place at the external tetrad of the quadruplex structure, at the junction between the quadruplex and the duplex region of the tested DNA substrate.…”

Fluorescence Detection of Potassium Ion Using the G-Quadruplex Structure

“…5A). 18 Around the 2006s, it was proposed that human telomere DNA exhibits polymorphism of tetraplex structures. 19 Figure 5 shows examples of such structures that include propeller and hybrid-type quadruplexes in addition to the basket-type structure.…”

G-Quadruplex in the NRF2 mRNA 5′ Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress

“…On the other hand, G residues in a G-quadruplex appear to be more likely oxidized than G residues in duplex DNA (80,81). 8-Oxoguanine in telomeric DNA influences the binding and activity of telomerase (82,83). In addition, 8-oxoguanine enhances the binding of helicase and DNA repair enzymes to telomeric DNA (84,85).…”