The formamidopyrimidines: purine lesions formed in competition with 8-oxopurines from oxidative stress.
The formamidopyrimidines: purine lesions formed in competition with 8-oxopurines from oxidative stress.
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DOI：
10.1021/ar2002182
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发表时间：
2012-04-17
影响因子：
18.3
通讯作者：
Greenberg, Marc M.
中科院分区：
文献类型：
--
作者：
Greenberg, Marc M.
DNA不断暴露于诱发结构损伤的物质中，这些物质来自生物体的内部和外部。内源性物质，如氧化性化学物质和外源性物质，如阳光中的紫外线，共同产生超过70种不同的天然核苷酸化学修饰。其中，在细胞DNA中检测到大约15个病变。这种结构性DNA损伤可能具有细胞毒性、致癌性，或者两者兼而有之，并且与越来越多的疾病有关。甲脒嘧啶（Fapy）病变是嘌呤经历氧化应激后导致的DNA病变家族。Fapy病变产生的产量与8-氧嘌呤相当，部分原因是由于某些方面的致突变性，因此受到了严格的研究审查。但是，尽管甲脒嘧啶和8-氧嘌呤的丰度相当，直到最近，人们对Fapy病变对涉及DNA的生化过程或对基因组物质的结构和稳定性的影响知之甚少。在这篇文章中，我们讨论了DNA中Fapy病变的检测及其形成机制。我们还描述了含有Fapy•dA或Fapy•dG的寡核苷酸的化学合成方法，以及利用这些化合物进行化学和生化研究的结果。这些实验表明，甲脒嘧啶降低了聚合酶的保真度，是DNA修复酶的底物。Fapy•dG在哺乳动物中的突变频率甚至高于8-oxodGuo （8-oxo-7,8-二氢-2 ' -脱氧鸟苷，8-氧嘌呤之一），这表明这种病变可能是一种有用的生物标志物，具有生物学意义。尽管有明显的相似之处，甲脒嘧啶一直生活在相应的8-氧嘌呤病变的阴影下。但最近合成含有Fapy•dA或Fapy•dG的寡核苷酸的方法的发展加速了对这些损伤的研究，揭示了甲脒嘧啶的修复效率与8-氧嘌呤一样高，在某些情况下，比8-氧嘌呤更快。Fapy•dG似乎是一种生化损伤，对其致突变性、修复和与DNA结构相互作用的进一步研究将更好地定义涉及这一DNA应激重要产物的细胞细节。
DNA is constantly exposed to agents that induce structural damage, from sources both internal and external to an organism. Endogenous species, such as oxidizing chemicals, and exogenous agents, such as ultraviolet rays in sunlight, together produce more than 70 distinct chemical modifications of native nucleotides. Of these, about 15 of the lesions have been detected in cellular DNA. This kind of structural DNA damage can be cytotoxic, carcinogenic, or both, and is being linked to an increasingly lengthy list of diseases. The formamidopyrimidine (Fapy) lesions are a family of DNA lesions that result after purines undergo oxidative stress. The Fapy lesions are produced in yields comparable to the 8-oxopurines, which, owing in part to a perception of mutagenicity in some quarters, have been subjected to intense research scrutiny. But despite the comparable abundance of the formamidopyrimidines and the 8-oxopurines, until recently very little was known about the effects of Fapy lesions on biochemical processes involving DNA or on the structure and stability of the genomic material. In this Account, we discuss the detection of Fapy lesions in DNA and the mechanism proposed for their formation. We also describe methods for the chemical synthesis of oligonucleotides containing Fapy•dA or Fapy•dG and the outcomes of chemical and biochemical studies utilizing these compounds. These experiments reveal that the formamidopyrimidines decrease the fidelity of polymerases and are substrates for DNA repair enzymes. The mutation frequency of Fapy•dG in mammals is even greater than that of 8-oxodGuo (8-oxo-7,8-dihydro-2′-deoxyguanosine, one of the 8-oxopurines), suggesting that this lesion could be a useful biomarker and biologically significant. Despite clear similarities, the formamidopyrimidines have lived in the shadow of the corresponding 8-oxopurine lesions. But the recent development of methods for synthesizing oligonucleotides containing Fapy•dA or Fapy•dG has accelerated research on these lesions, revealing that the formamidopyrimidines are repaired as efficiently and, in some cases, more rapidly than the 8-oxopurines. Fapy•dG appears to be a lesion of biochemical consequence, and further study of its mutagenicity, repair, and interactions with DNA structure will better define the cellular details involving this important product of DNA stress.
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