The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals.
The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals.
复制标题
DOI：
10.1042/bj20101116
复制
发表时间：
2010-11-15
期刊：
影响因子：
--
通讯作者：
Ristow M
中科院分区：
文献类型：
--
作者：
Thierbach R;Drewes G;Fusser M;Voigt A;Kuhlow D;Blume U;Schulz TJ;Reiche C;Glatt H;Epe B;Steinberg P;Ristow M
DNA修复机制使细胞能够通过保护其免受可能导致恶性生长的突变来维持其遗传信息。最近的证据表明，特定的DNA修复酶含有ISCs（铁硫簇）。核蛋白frataxin是ISCs的线粒体生物合成所必需的。Frataxin缺乏会导致一种名为弗里德赖希共济失调的神经退行性疾病。在年轻时发生的各种类型的癌症与这种疾病有关，因此与共济失调蛋白缺乏有关。携带肝细胞特异性破坏frataxin基因的小鼠由于未解决的原因发展为多个肝脏肿瘤。在本研究中，我们表明小鼠肝脏中的共济失调蛋白缺乏与氧化DNA碱基损伤的基础水平增加有关。因此，过表达人共济失调蛋白的真核V79成纤维细胞显示这些修饰的基础水平降低，而用人共济失调蛋白转化的原核肠道沙门氏菌血清型鼠伤寒TA 104菌株显示突变率降低。过表达共济蛋白的V79细胞中氧化DNA碱基修饰的修复率显著高于对照细胞。最后，发现与ISC非依赖性修复酶8-氧代鸟嘌呤糖基化酶相关的切割活性未被共济失调蛋白过表达改变。这些发现表明，frataxin调节DNA修复机制可能是由于其对ISC依赖性修复蛋白的影响，将线粒体功能障碍与DNA修复和肿瘤启动联系起来。
DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron–sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation.