Long-range oxidative damage to DNA:: effects of distance and sequence
Long-range oxidative damage to DNA:: effects of distance and sequence
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DOI：
10.1016/s1074-5521(99)80005-2
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发表时间：
1999-02-01
影响因子：
--
通讯作者：
Barton, JK
中科院分区：
文献类型：
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作者：
Núñez, ME;Hall, DB;Barton, JK
简介：体内DNA的氧化损伤会导致突变和癌症。DNA损伤和修复研究尚未揭示永久性氧化损伤是否是由电荷长距离迁移造成的，光激发*Rh(III)和基态Ru(III)嵌入物先前都被证明通过DNA介导的电子转移氧化寡核苷酸双链中远程位置的鸟嘌呤碱基。在这里，我们检查了更长的电荷传输距离，并探索了反应对干预序列的敏感性。结果：在一系列包含悬挂式插层光氧化剂的DNA双链中检测到了氧化损伤。这些研究表明，对距离的依赖性很小，与氧化剂相对于损伤部位5‘-GG-3’的定相方向无关，但DNA插入序列对鸟嘌呤氧化的产率有显著影响。与通过其他基本步骤相比，通过多个5‘-TA-3’步骤实质上减少了氧化。我们在200埃的距离上观察到*Rh(III)和Ru(III)双链鸟嘌呤的氧化。氧化鸟嘌呤的分布在5-35℃之间随温度的变化而变化，随着温度的升高，发生远程损伤(>；100埃)的比例增加。结论：鸟嘌呤被氧化是DNA介导的较远距离(如200埃)电荷传输的结果。虽然长程电荷转移依赖于距离，但它似乎受到干预序列和序列依赖动力学的调节，这些发现对体内DNA损伤具有重要意义。
Introduction: Oxidative damage to DNA in vivo can lead to mutations and cancer. DNA damage and repair studies have not yet revealed whether permanent oxidative lesions are generated by charges migrating over long distances, Both photoexcited *Rh(III) and ground-state Ru(III) intercalators were previously shown to oxidize guanine bases from a remote site in oligonucleotide duplexes by DNA-mediated electron transfer. Here we examine much longer charge-transport distances and explore the sensitivity of the reaction to intervening sequences.Results: Oxidative damage was examined in a series of DNA duplexes containing a pendant intercalating photooxidant. These studies revealed a shallow dependence on distance and no dependence on the phasing orientation of the oxidant relative to the site of damage, 5'-GG-3', The intervening DNA sequence has a significant effect on the yield of guanine oxidation, however. Oxidation through multiple 5'-TA-3' steps is substantially diminished compared to through other base steps. We observed intraduplex guanine oxidation by tethered *Rh(III) and Ru(III) over a distance of 200 Angstrom. The distribution of oxidized guanine varied as a function of temperature between 5 and 35 degrees C, with an increase in the proportion of long-range damage (> 100 Angstrom) occurring at higher temperatures.Conclusions: Guanines are oxidized as a result of DNA-mediated charge transport over significant distances (e.g, 200 Angstrom). Although long-range charge transfer is dependent on distance, it appears to be modulated by intervening sequence and sequence-dependent dynamics, These discoveries hold important implications with respect to DNA damage in vivo.