DNA polymerase V allows bypass of toxic guanine oxidation products in vivo
DNA polymerase V allows bypass of toxic guanine oxidation products in vivo
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DOI：
10.1074/jbc.m700575200
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发表时间：
2007-04-27
影响因子：
4.8
通讯作者：
Essigmann, John M.
中科院分区：
文献类型：
--
作者：
Neeley, William L.;Delaney, Sarah;Essigmann, John M.
在代谢过程中产生的活性氧和氮自由基，如呼吸和炎症，与DNA结合，主要在鸟嘌呤位点形成许多病变。了解聚合酶在这些产物突变过程中的作用，可以阐明氧化应激与癌症相关的分子机制。利用M13病毒基因组包含单个DNA损伤和具有特异性聚合酶（pol）敲除的大肠杆菌菌株，我们发现pol V是有效绕过体内结构多样、高度诱变的鸟嘌呤氧化产物所必需的。我们还发现，pol IV参与了两个螺亚胺双乙酰胆碱病变的旁路。此外，我们报道了一种病变，5-胍-4-硝基咪唑，是多种SOS聚合酶的底物，其中pol II是无错误复制所必需的，而pol V是通过该病变进行易出错复制所必需的。这些结果揭示了pol V在鸟嘌呤氧化诱变机制中的主要作用，pol II和pol IV的次要作用。
Reactive oxygen and nitrogen radicals produced during metabolic processes, such as respiration and inflammation, combine with DNA to form many lesions primarily at guanine sites. Understanding the roles of the polymerases responsible for the processing of these products to mutations could illuminate molecular mechanisms that correlate oxidative stress with cancer. Using M13 viral genomes engineered to contain single DNA lesions and Escherichia coli strains with specific polymerase ( pol) knockouts, we show that pol V is required for efficient bypass of structurally diverse, highly mutagenic guanine oxidation products in vivo. We also find that pol IV participates in the bypass of two spiroiminodihydantoin lesions. Furthermore, we report that one lesion, 5-guanidino-4-nitroimidazole, is a substrate for multiple SOS polymerases, whereby pol II is necessary for error-free replication and pol V for error-prone replication past this lesion. The results spotlight a major role for pol V and minor roles for pol II and pol IV in the mechanism of guanine oxidation mutagenesis.