title: Guanine-specific DNA damage induced by gamma-irradiated histone.
abstract: In gamma-irradiation, *OH is directly generated from water and causes DNA damage leading to carcinogenesis. Exposure of proteins to gamma-irradiation, in the presence of oxygen, gives high yields of hydroperoxides. To clarify whether these hydroperoxides, particularly those formed on DNA-binding histone proteins, participate in gamma-irradiation-induced carcinogenesis, experiments using 32P-labelled DNA fragments obtained from human cancer-related genes were undertaken. Histone protein-hydroperoxides induced significant DNA damage in the presence of Cu(I). Histone H1- and H3-hydroperoxides showed stronger DNA damage compared with histone H2A- and H4-hydroperoxides at 0.7 muM. Histone H1-hydroperoxides caused Cu(I)-dependent DNA damage predominantly at guanine residues, especially at 5'-GGC-3', 5'-GGA-3', 5'-GGT-3' and single G bases. In contrast, histone H3-hydroperoxides/Cu(I) induced DNA damage at 5'-G in GG sequences; this sequence specificity is identical with that generated by 2,2'-azobis (2-amidinopropane) dihydrochloride, which is known to produce peroxyl radicals (RO2*). The difference in site specificity of DNA damage induced by histone H1- and H3-hydroperoxides may arise from their amino acid composition or their mode of binding to DNA. The histone H1-hydroperoxides/Cu(I) system also induced 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in calf thymus DNA. It is concluded that histone protein-hydroperoxides can induce guanine-specific DNA damage, which may contribute to gamma-irradiation-induced carcinogenesis.
authors.affiliation: Department of Environmental and Molecular Medicine, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Furukawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.forename: Shinji
authors.initials: S
authors.lastname: Oikawa
authors.forename: Catherine
authors.initials: C
authors.lastname: Luxford
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davies
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000578:Amidines / Q000737:chemistry; D000818:Animals; D002417:Cattle; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism / Q000528:radiation effects*; D004249:DNA Damage / Q000528:radiation effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D005720:Gamma Rays; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006147:Guanine / Q000737:chemistry* / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000528:radiation effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D000578:Amidines; D006657:Histones; D006147:Guanine; C046728:2,2'-azobis(2-amidinopropane); D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C427203:calf thymus DNA; D006861:Hydrogen Peroxide; D003849:Deoxyguanosine