Molecular mechanism for suppressing oxidative DNA damage

氧化DNA损伤被认为是导致癌症、衰老和神经退化的原因。研究表明，DNA氧化损伤会在癌组织中积累。例如，与周围正常组织相比，肺癌组织中观察到的氧化碱基损伤水平更高。另一项研究报告，与正常组织相比，乳腺癌组织DNA中8-oxoG，8-羟基腺嘌呤和2，6-二氨基-4-羟基-5-甲酰胺基嘧啶的含量增加了9倍。此外，人类患癌症的累积风险随着年龄的增长而急剧增加。从基因的角度来说，癌症可以被认为是一种衰老的退行性疾病。根据主要测量8-oxo-7，8-二氢-2‘-脱氧鸟苷5’-三磷酸(8-oxo-dGTP)在正常细胞代谢过程中在细胞的核苷酸池中形成的研究，有证据表明氧化DNA损伤随着年龄的增加而积累。当8-oxo-dGTP结合到DNA中时，会导致突变。生物体拥有8-氧代…More-dGTP酶，一种专门将8-oxo-dGTP降解为8-oxo-dGMP的酶。通过基因打靶的方法，建立了MTH1基因和8-oxo-dGTP酶活性缺失的小鼠株系。在两个独立分离的MTH1-/-ES细胞系中观察到HPRT基因自发突变的频率大约是MTH1+/+细胞的2倍。然后，我们检查了衍生的突变小鼠对自发肿瘤发生的敏感性。由大约50只雄性和50只雌性组成的野生型或突变小鼠被保存在SPF条件下，并在1.5年后解剖。MTH1+/+和MTH1-/-小鼠的存活率无显著差异。然而，病理检查显示，肿瘤的发生率在统计学上有显著差异。野生型和突变型小鼠在肺部的肿瘤形成频率有明显差异，而MTH1-/-小鼠的胃和肝脏也可能形成更多的肿瘤。8-oxo-dGTP酶在保护动物免受氧诱导的DNA损伤所致的自发肿瘤发生中起着重要作用。MTH1基因缺陷小鼠为探讨MTH1蛋白在正常和氧化应激下的体内作用提供了一个新的有用的模型系统。较少

Oxidative DNA damage is thought to contribute to carcinogenesis, aging, and neurological degeneration. Studies have shown that oxidative DNA damage accumulates in cancerous tissue. For example, higher levels of oxidative base damage were observed in lung cancer tissue compared with surrounding normal tissue. Another study reported a 9-fold increase in 8-oxoG, 8-hydroxyadenine, and 2,6-diamino-4-hydroxy-5-formamidopyrimidine in DNA from breast cancer tissue compared with normal tissue. Further, the cumulative risk of cancer increases dramatically with age in humans. In genreal terms cancer can be regarded as a degenerative disease of ageing. There is evidence for the accumulation of oxidative DNA damage with age based on studies mainly measuring an increase in 8-oxoG.8-Oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is formed in the nucleotide pool of a cell during normal cellular metabolism. When incorporated into DNA, 8-oxo-dGTP causes mutation. Organisms posseces 8-oxo … More -dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP. By means of gene targeting, we established mouse lines deficient in the MTH1 gene, and 8-oxo-dGTPase activity. An approximately 2-fold higher frequency of spontaneous mutations in the HPRT gene was observed in two independently isolated MTH1-/- ES cell lines, compared with the value of MTH1+/+ cells. We then examined susceptibility of the derived mutant mice to spontaneous tumorigenesis. Wild type or mutant mice consisting of approximately 50 male and 50 female were maintained under SPF conditions and necropsied after 1.5 years. No significant difference in survival rates of MTH1+/+ and MTH1-/- mice. However, pathological examination revealed a statistically significant difference in the incidence of tumors. A distinct difference in the frequency of tumor formation in lungs between wild-type and mutant mice was observed while more tumors were likely to be formed in the stomach and in liver of MTH1-/- mice as well. 8-Oxo-dGTPase appears to play an important role to protect animals from the spontaneous tumorigenesis caused by the oxygen-induced DNA damage.The MTH1-deficient mouse provides a new and useful model system in which to explore the in vivo role of the MTH1 protein in normal and under oxidative stress. Less