Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids
Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids
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DOI：
10.1515/bc.2006.050
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发表时间：
2006-04-01
影响因子：
3.7
通讯作者：
Nakatsu, Y
中科院分区：
文献类型：
--
作者：
Nakabeppu, Y;Sakumi, K;Nakatsu, Y
基因组及其前体核苷酸高度暴露于活性氧物质，活性氧物质作为氧气呼吸或宿主防御中的分子执行器的副产物以及通过环境暴露于电离辐射和化学品而产生。为了抵消核酸中的这种氧化损伤，哺乳动物细胞配备了三种不同的酶。MTH 1蛋白水解氧化的嘌呤核苷三磷酸，如8-氧代-29-脱氧鸟苷三磷酸和2-羟基-29-脱氧腺苷三磷酸（2-OH-dATP），成为相应的单磷酸。我们观察到MTH 1基因敲除小鼠自发性癌变的易感性增加，表现出A：T T C：G和G：C T T：A颠换突变的发生率增加。8-由OGG 1基因编码的氧代鸟嘌呤（8-oxoG）DNA糖基化酶和由MUTYH基因编码的腺嘌呤DNA糖基化酶负责抑制由基因组中8-oxoG积累引起的G：C至T：A颠换。这些酶的缺乏分别导致小鼠肺和肠道中的肿瘤发生增加。MUTYH缺乏还可能通过2-OH-dATP的错误掺入增加G：C至T：A的颠换，尤其是在肠道中，因为MUTYH可以切除基因组DNA中与鸟嘌呤相反的2-羟基腺嘌呤，并且修复活性因常染色体隐性遗传性结直肠腺瘤性息肉病患者中发现的突变而选择性受损。
Genomes and their precursor nucleotides are highly exposed to reactive oxygen species, which are generated both as byproducts of oxygen respiration or molecular executors in the host defense, and by environmental exposure to ionizing radiation and chemicals. To counteract such oxidative damage in nucleic acids, mammalian cells are equipped with three distinct enzymes. MTH1 protein hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-29-deoxyguanosine triphosphate and 2-hydroxy-29-deoxyadenosine triphosphate (2-OH-dATP), to the corresponding monophosphates. We observed increased susceptibility to spontaneous carcinogenesis in MTH1-null mice, which exhibit an increased occurrence of A: T T C: G and G: C T T: A transversion mutations. 8-Oxoguanine (8-oxoG) DNA glycosylase, encoded by the OGG1 gene, and adenine DNA glycosylase, encoded by the MUTYH gene, are responsible for the suppression of G: C to T: A transversions caused by the accumulation of 8-oxoG in the genome. Deficiency of these enzymes leads to increased tumorigenesis in the lung and intestinal tract in mice, respectively. MUTYH deficiency may also increase G: C to T: A transversions through the misincorporation of 2-OH-dATP, especially in the intestinal tract, since MUTYH can excise 2-hydroxyadenine opposite guanine in genomic DNA and the repair activity is selectively impaired by a mutation found in patients with autosomal recessive colorectal adenomatous polyposis.