DNA Damage by Reactive Oxygen Species and Some Protective Responses

Title DNA Damage by Reactive Oxygen Species and Some Protective Responses
Lecturer Prof. Stuart Linn(Deapartment of Molecular and Cellular Biology, University of California, Berkeley)
Language English
Date&Time 09/13/2013 (Fri) 13:30~14:30
Venue Large seminar room
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.
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.

Contact 原核生物分子遺伝学
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