Guanine-specific DNA damage induced by gamma-irradiated histone.
Guanine-specific DNA damage induced by gamma-irradiated histone.
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发表时间：
2005
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通讯作者：
A. Furukawa;Y. Hiraku;S. Oikawa;C. Luxford;M. Davies;S. Kawanishi
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作者：
A. Furukawa;Y. Hiraku;S. Oikawa;C. Luxford;M. Davies;S. Kawanishi
在伽马射线照射下，*OH 直接从水中产生并导致 DNA 损伤，从而导致致癌。在有氧存在的情况下，将蛋白质暴露于伽马射线下，可产生高产率的氢过氧化物。为了澄清这些氢过氧化物，特别是在 DNA 结合组蛋白上形成的氢过氧化物，是否参与伽马射线照射诱导的致癌作用，使用从人类癌症相关基因获得的 32P 标记的 DNA 片段进行了实验。在 Cu(I) 存在下，组蛋白氢过氧化物会诱导显着的 DNA 损伤。与 0.7 μM 的组蛋白 H2A- 和 H4- 氢过氧化物相比，组蛋白 H1- 和 H3- 氢过氧化物表现出更强的 DNA 损伤。组蛋白 H1-氢过氧化物主要在鸟嘌呤残基处引起 Cu(I) 依赖性 DNA 损伤，特别是在 5'-GGC-3'、5'-GGA-3'、5'-GGT-3' 和单个 G 碱基处。相比之下，组蛋白 H3-氢过氧化物/Cu(I) 会诱导 GG 序列中 5'-G 处的 DNA 损伤；该序列特异性与 2,2'-偶氮二（2-脒基丙烷）二盐酸盐产生的序列特异性相同，已知后者会产生过氧自由基（RO2*）。组蛋白 H1-和 H3-氢过氧化物诱导的 DNA 损伤位点特异性的差异可能源于它们的氨基酸组成或其与 DNA 的结合模式。组蛋白 H1-氢过氧化物/Cu(I) 系统还诱导小牛胸腺 DNA 中 8-oxo-7,8-diHydro-2'-deoxyguanosine 的形成。结论是组蛋白氢过氧化物可以诱导鸟嘌呤特异性 DNA 损伤，这可能有助于伽马射线照射诱发的癌变。
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.