Light-induced oxidation of the telomeric G4 DNA in complex with Zn(II) tetracarboxymethyl porphyrin

Abstract

Structure-specific ligands are convenient tools for the recognition, targeting or probing of non-canonical DNA structures. Porphyrin derivatives exhibit a preference for interaction with G-quadruplex (G4) structures over canonical duplex DNA and are able to cause photoinducible damage to nucleic acids. Here, we show that Zn(II) 5,10,15,20-tetrakis(N-carboxymethyl-4-pyridinium)porphyrin (ZnP1) interacts with different conformations of the telomeric sequence d(TAGGG(TTAGGG)3) at submicromolar concentrations without any detectible disturbance of the particular fold. Among different folds, potassium (3+1) hybrid G4-structure. reveal the highest affinity to ZnP1. The pattern of guanine oxidation is specific for each telomeric DNA conformation and may serve as an additional tool for probing the G4 topology. The potassium (3+1) and parallel G4 conformations are more susceptible to light-induced oxidation than the sodium G4 conformation or double helix of the telomeric DNA. The major products of the guanine modifications are spiroiminodihydantoin (Sp) and 8-oxoguanine (8-oxoG). ZnP1-induced oxidation of guanines results in the structural rearrangement of parallel and (3+1) G4 conformations yielding an antiparallel-like G4 conformation. The mechanism of the observed light-induced conformational changes is discussed.

Binding and Beyond: What Else Can G‐Quadruplex Ligands Do?

“…As summarized in the sections below, developments in the field of G4 ligand design have indeed permitted the design of several G4‐targeting agents to modify nucleic acid in a more selective manner, for example by metalation, alkylation or scission . Furthermore, since guanine is the most readily oxidized DNA base, it is not surprising that efforts have also been made to utilize G4 ligands as a mean to direct the site‐selective modification of nucleic acids in this way . The following sections explore the progress made in these areas.…”

“…Indeed, the field has recently taken steps towards engineering G4 ligands that exert different kinds of control on G4 that could be exploited toward biological and therapeutic ends. Such approaches harness the selectivity of G4‐binding chemotypes to trigger a further molecular event, such as modification of the G4 by alkylation or oxidation, or as the basis for the localized generation of singlet‐oxygen by photosensitization . Furthermore, a small number of responsive G4 ligands have also been described.…”

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

“…The Zn(II)-porphyrin complex-induced oxidation of guanines in the GQ of TA(htel-21) yielded o 8 G and its further oxidized product, the spiroiminodihydantoin. The oxidized bases prompted structural rearrangements of the parallel and hybrid TA(htel-21) GQs into an antiparallel-like conformation [ 289 ], such as what was observed earlier with o 8 G-containing htel-21 GQs [ 26 ].…”

G-quadruplexes: a promising target for cancer therapy

“…Porphyrins are well known photosensitizer used in PDT. Specific porphyrin derivates have been developed to target telomeric G4 (TMPipEOPP [ 67 ], ZnP1 [ 68 ]). TMPipEOPP binds to telomeric G4.…”