Oxidative damage generated by an oxo-metalloporphyrin onto the human telomeric sequence.
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.
Vialas
C
C
Laboratoire de Chimie de Coordination du CNRS, Toulouse, France.
Pratviel
G
G
Meunier
B
B
D001483:Base Sequence / Q000187:drug effects; D002414:Cations, Monovalent; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D003855:Deoxyribose / Q000378:metabolism; D054856:G-Quadruplexes; D006801:Humans; D006868:Hydrolysis; D006900:Hydroxylation / Q000187:drug effects; D007364:Intercalating Agents / Q000633:toxicity; D008665:Metalloporphyrins / Q000633:toxicity*; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009692:Nucleic Acid Heteroduplexes / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D016615:Telomere / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013941:Thymine / Q000378:metabolism
D002414:Cations, Monovalent; D007364:Intercalating Agents; D008665:Metalloporphyrins; D009692:Nucleic Acid Heteroduplexes; D003855:Deoxyribose; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D004247:DNA; D013941:Thymine