Neighboring base sequence effect on DNA damage

Guanine is the most strongly oxidized base in DNA; generation of a guanine radical cation as an intermediate in an oxidation reaction leads to migration through a resulting cationic hole in the DNA π-stack until it is trapped by irreversible reaction with water or other free radicals. In the case of normal sequences, the primary position of Guanine oxidations by one-electron oxidants such as carbonate radical anions, BPT(7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene), and riboflavin are 5′-G in GG doublets and the central G in a GGG triplet. According to results, the properties of guanine oxidation on abasic site containing sequences are independent from the position of AP(apurinic/apyrimidinic) site in the presence of carbonate radical anions under a short irradiation time, although this radical is exposed to solvent by the existence of an abasic site. The lack of abasic site effect on guanine oxidative damage by the carbonate radical may be due to a sequence-independent property of the initial electron transfer rate in the hole injection step, or may relate to an electron transfer mechanism with large reorganization energy dependency. Consequently, the carbonate radical anions may easily migrate to another single G in the charge re-distribution step. Meanwhile, there is a strong dependency on the presence of an AP(apurinic/apyrimidinic) site in the cleavage patterns of guanine oxidations by physically large oxidizing agents, such as BPT(7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene) and riboflavin. These radicals show strong AP(apurinic/apyrimidinic) site dependency and clear G-site selectivity. Communicated by Ramaswamy H. Sarma

鸟嘌呤（Guanine）是脱氧核糖核酸（DNA）中最易被氧化的碱基；氧化反应中生成的鸟嘌呤自由基阳离子（guanine radical cation）作为中间产物，会在DNA π堆叠（DNA π-stack）中通过所产生的阳离子空穴迁移，直至与水或其他自由基发生不可逆反应而被捕获。在正常碱基序列中，碳酸根自由基阴离子（carbonate radical anions）、BPT(7,8,9,10-四羟基四氢苯并[a]芘)（BPT(7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene)）以及核黄素（riboflavin）等单电子氧化剂引发的鸟嘌呤氧化，其主要位点为GG二联碱基中的5′-G以及GGG三联碱基中的中央G。研究结果表明，在短时间辐照条件下，含无碱基位点（abasic site）序列的鸟嘌呤氧化特性不受AP(脱嘌呤/脱嘧啶)位点位置的影响，尽管无碱基位点的存在会使该自由基暴露于溶剂中。碳酸根自由基阴离子对鸟嘌呤氧化损伤未表现出无碱基位点效应，这一现象可能源于空穴注入步骤中初始电子转移速率不依赖序列特性，或是与依赖大重组能（reorganization energy）的电子转移机制相关。据此，碳酸根自由基阴离子可在电荷再分配步骤中轻易迁移至其他单个鸟嘌呤位点。与此同时，对于BPT(7,8,9,10-四羟基四氢苯并[a]芘)与核黄素这类体积较大的氧化剂，其引发的鸟嘌呤氧化裂解模式与AP(脱嘌呤/脱嘧啶)位点的存在具有极强相关性，这类氧化剂表现出显著的AP位点依赖性与明确的鸟嘌呤位点选择性。本文由Ramaswamy H. Sarma转交。