Reactive oxygen species cause DNA damage that accumulates with age and leads to oncogenesis. DNA-bound Fe2+ catalyzing the univalent reduction of H2O2 forms much of the damage. Examining DNA nicking, we find that cleavage in μM H2O2 occurs at the dT within the sequence RTGR (R=purine), a necessary motif frequently found in promoters for responses of many genes to iron-or oxygen stress. By contrast, with mM H2O2, cleavage occurs at a nucleoside 5’ to one of the dG moieties in RGGG, a sequence present in telomere repeats, hinting at an involvement in telomere shortening and aging. NADH directly or indirectly regenerates Fe2+ from the Fe3+ product and, to respond to H2O2 exposure, E.coli adjusts its metabolism so as to increases its NADPH: NADH ratio by 6- or 92-fold upon exposure to 0.5 or 5mM H2O2 , respectively. NMR studies show that Fe3+ is sequestered by the 2’-phosphate group of NADPH, removing it from close proximity to the redox-active nicotinamide ring. In eukaryotes, NADH is depleted indirectly by polymerization of NAD+ to poly (ADP-ribose), which also prevents activation of NAD+ Sir proteins that can cause epigenetic changes. These observations might explain why excessive consumption of antioxidants such as vitamins A, C, or E can stimulate carcinogenesis.
Refferences:
Rai, P., Wemmer, D. E. and Linn, S. (2005) Preferential binding and structural distortion by Fe2+ at RGGG-containing DNA sequences correlates with enhanced oxidative cleavage at such sequences. Nuc. Acids Res. 33, 497-510.
Rai, P., Cole, T. D., Wemmer, D. E. and Linn, S. (2001) Localization of Fe2+ at an RTGR Sequence within a DNA duplex explains preferential cleavage by Fe2+ and H202. J. Mol. Biol. 312, 1089-1101.
奈良先端科学技術大学院大学