TY - JOUR
T1 - Radicals derived from histone hydroperoxides damage nucleobases in RNA and DNA
AU - Luxford, C
AU - Dean, R T
AU - Davies, Michael Jonathan
PY - 2000/7
Y1 - 2000/7
N2 - Exposure of individual histone proteins (H1, H2A, H2B, H3, or H4) and histone octamers (consisting of two molecules each of H2A, H2B, H3, and H4) to hydroxyl radicals, generated by gamma-irradiation, in the presence of O(2) generates protein-bound hydroperoxides in a dose-dependent fashion; this is in accord with previous studies with other proteins. These histone hydroperoxides are stable in the absence of exogenous catalysts (e.g., heat, light, and transition metal ions), but in the presence of these agents decompose rapidly to give a variety of radicals which have been identified by EPR spin trapping. Histone hydroperoxide-derived radicals generated on decomposition of the hydroperoxides with Cu(+) react with both pyrimidine and purine nucleobases. Thus, with uridine the histone hydroperoxide-derived radicals undergo addition across the C(5)-C(6) double bond of the pyrimidine ring to give cross-linked adduct species which have been identified by EPR spectroscopy. HPLC analysis of the products generated on reaction of histone hydroperoxide-derived radicals with 2'-deoxyguanosine, or intact calf thymus DNA, has shown that significant levels of the mutagenic oxidized DNA base 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) are formed, with the yield dependent on the individual histone protein, the presence of hydroperoxide functions, and the concentration of metal ion. These studies demonstrate that initial oxidative damage to individual histone proteins or histone octamers can result in the transfer of oxidative damage to associated DNA via the formation and subsequent decomposition of protein hydroperoxides to reactive radicals, and provide a novel route for the formation of mutagenic lesions in DNA.
AB - Exposure of individual histone proteins (H1, H2A, H2B, H3, or H4) and histone octamers (consisting of two molecules each of H2A, H2B, H3, and H4) to hydroxyl radicals, generated by gamma-irradiation, in the presence of O(2) generates protein-bound hydroperoxides in a dose-dependent fashion; this is in accord with previous studies with other proteins. These histone hydroperoxides are stable in the absence of exogenous catalysts (e.g., heat, light, and transition metal ions), but in the presence of these agents decompose rapidly to give a variety of radicals which have been identified by EPR spin trapping. Histone hydroperoxide-derived radicals generated on decomposition of the hydroperoxides with Cu(+) react with both pyrimidine and purine nucleobases. Thus, with uridine the histone hydroperoxide-derived radicals undergo addition across the C(5)-C(6) double bond of the pyrimidine ring to give cross-linked adduct species which have been identified by EPR spectroscopy. HPLC analysis of the products generated on reaction of histone hydroperoxide-derived radicals with 2'-deoxyguanosine, or intact calf thymus DNA, has shown that significant levels of the mutagenic oxidized DNA base 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) are formed, with the yield dependent on the individual histone protein, the presence of hydroperoxide functions, and the concentration of metal ion. These studies demonstrate that initial oxidative damage to individual histone proteins or histone octamers can result in the transfer of oxidative damage to associated DNA via the formation and subsequent decomposition of protein hydroperoxides to reactive radicals, and provide a novel route for the formation of mutagenic lesions in DNA.
KW - Animals
KW - Cattle
KW - DNA
KW - DNA Damage
KW - Deoxyguanosine
KW - Dose-Response Relationship, Radiation
KW - Electron Spin Resonance Spectroscopy
KW - Free Radicals
KW - Histones
KW - Nucleic Acids
KW - Oxidation-Reduction
KW - Peroxides
M3 - Journal article
C2 - 10898600
SN - 0893-228X
VL - 13
SP - 665
EP - 672
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
IS - 7
ER -