SUPEROXIDE AND THE PRODUCTION OF OXIDATIVE DNA-DAMAGE
SUPEROXIDE AND THE PRODUCTION OF OXIDATIVE DNA-DAMAGE
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DOI：
10.1128/jb.177.23.6782-6790.1995
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发表时间：
1995-12-01
影响因子：
3.2
通讯作者：
IMLAY, JA
中科院分区：
文献类型：
--
作者：
KEYER, K;GORT, AS;IMLAY, JA
传统的DNA氧化损伤模型假定超氧化物(O-2(-))作为铁的还原剂，随后通过将电子转移到H_2O_2来产生羟基自由基。···确实，缺乏超氧化物歧化酶(SOD)的突变体比野生型细胞更容易受到过氧化氢氧化的伤害，甚至内源性氧化剂对DNA的破坏速度也很快，如果修复DNA氧化损伤的酶不活跃，突变体就不能此外，当通过施加厌氧消除O-2(-)后，SOD突变体对DNA损伤的超敏持续至少20分钟时，过量O-2(-)导致损伤的机制受到质疑。这一行为与标准模型相矛盾，标准模型要求在暴露于过氧化氢期间存在O-2(-)以重新还原细胞内的铁。显然，DNA氧化是由O-2(-)以外的还原剂驱动的，这使得O-2(-)促进损伤的机制尚未解决。一种可能性是，O-2(-)通过其从铁-硫簇中浸出铁的公认能力，增加了可用于催化产生羟基自由基的游离铁的量，用铁运输突变体进行的实验证实，增加游离铁浓度具有加速DNA氧化的效果，因此，O-2(-)可能只有在超过超氧化物歧化酶熟练掌握细胞中发现的剂量时才具有遗传毒性，在这些有限的情况下，它可能通过增加DNA结合铁量来促进DNA损伤。
The conventional model of oxidative DNA damage posits a role for superoxide (O-2(-)) as a reductant for iron, which subsequently generates a hydroxyl radical by transferring the electron to H2O2. The hydroxyl radical then attacks DNA, Indeed, mutants of Escherichia coli that lack superoxide dismutase (SOD) were 10-fold more vulnerable to DNA oxidation by H2O2 than were wild-type cells, Even the pace of DNA damage by endogenous oxidants was great enough that the SOD mutants could not tolerate air if enzymes that repair oxidative DNA lesions were inactive, However, DNA oxidation proceeds in SOD-proficient cells without the involvement of O-2(-), as evidenced by the failure of SOD overproduction or anaerobiosis to suppress damage by H2O2. Furthermore, the mechanism by which excess O-2(-) causes damage was called into question when the hypersensitivity of SOD mutants to DNA damage persisted for at least 20 min after O-2(-) had been dispelled through the imposition of anaerobiosis. That behavior contradicted the standard model, which requires that O-2(-) be present to rereduce cellular iron during the period of exposure to H2O2. Evidently, DNA oxidation is driven by a reductant other than O-2(-), which leaves the mechanism of damage promotion by O-2(-) unsettled. One possibility is that, through its well-established ability to leach iron from iron-sulfur clusters, O-2(-) increases the amount of free iron that is available to catalyze hydroxyl radical production, Experiments with iron transport mutants confirmed that increases in free-iron concentration have the effect of accelerating DNA oxidation, Thus, O-2(-) may be genotoxic only in doses that exceed those found in SOD-proficient cells, and in those limited circumstances it may promote DNA damage by increasing the amount of DNA-bound iron,