Lack of the DNA glycosylases MYH and OGG1 in the cancer prone double mutant mouse does not increase mitochondrial DNA mutagenesis
Lack of the DNA glycosylases MYH and OGG1 in the cancer prone double mutant mouse does not increase mitochondrial DNA mutagenesis
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DOI：
10.1016/j.dnarep.2011.12.001
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发表时间：
2012-03-01
期刊：
影响因子：
3.8
通讯作者：
Eide, Lars
中科院分区：
文献类型：
--
作者：
Halsne, Ruth;Esbensen, Ying;Eide, Lars
活性氧（ROS）作为有氧代谢过程中的天然副产物形成，并容易诱导DNA中的预致突变碱基损伤。8-氧代鸟嘌呤DNA糖基化酶（OGG 1）和MutY同源物1（MYH）协同防止小鼠的诱变和癌症形成。它们在线粒体和细胞核中的定位表明，线粒体中的突变！为了验证线粒体DNA（mtDNA）与myh（-/-）/ogg 1（-/-）双基因敲除小鼠的致癌作用，我们对幼年（1月龄）和成年（6月龄）wt和myh（-/-）/ogg 1（-/-）小鼠的mtDNA突变和线粒体功能进行了分析。令我们惊讶的是，OGG 1和MYH的缺失对这些小鼠的mtDNA突变率没有影响，即使在癌症发作时也是如此。提示mtDNA突变与myh（-/-）/ogg 1（-/-）小鼠的致癌作用无关。与这些结果一致，线粒体功能在癌组织肝脏和肺中未受影响，而在成年myh（-/-）/ogg 1（-/-）小鼠的脑线粒体中观察到呼吸能力显著降低。我们的研究结果表明，线粒体DNA突变与myh（-/-）/ogg 1（-/-）小鼠的癌症发展无关，脑线粒体功能的损害可能与该品系小鼠的核DNA突变有关。OGG 1和MYH似乎在线粒体中具有抗突变功能。(C)2011爱思唯尔有限公司版权所有。
Reactive oxygen species (ROS) are formed as natural byproducts during aerobic metabolism and readily induce premutagenic base lesions in the DNA. The 8-oxoguanine DNA glycosylase (OGG1) and MutY homolog 1 (MYH) synergistically prevent mutagenesis and cancer formation in mice. Their localization in the mitochondria as well as in the nucleus suggests that mutations in mitochondria! DNA (mtDNA) contribute to the carcinogenesis in the myh(-/-)/ogg1(-/-) double knockout mouse.In order to test this hypothesis, we analyzed mtDNA mutagenesis and mitochondrial function in young (1 month) and adult (6 months) wt and myh(-/-)/ogg1(-/-) mice. To our surprise, the absence of OGG1 and MYH had no impact on mtDNA mutation rates in these mice, even at the onset of cancer. This indicates that mtDNA mutagenesis is not responsible for the carcinogenesis of myh(-/-)/ogg1(-/-) mice. In line with these results, mitochondrial function was unaffected in the cancerous tissues liver and lung, whereas a significant reduction in respiration capacity was observed in brain mitochondria from the adult myh(-/-)/ogg1(-/-) mouse. The reduced respiration capacity correlated with a specific reduction (-25%) in complex I biochemical activity in brain mitochondria.Our results demonstrate that mtDNA mutations are not associated with cancer development in myh(-/-)/ogg1(-/-) mice, and that impairment of mitochondrial function in brain could be linked to nuclear DNA mutations in this strain. OGG1 and MYH appear to be dispensable for antimutator function in mitochondria. (C) 2011 Elsevier B.V. All rights reserved.