Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis
Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis
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DOI：
10.1172/jci31604
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发表时间：
2007-09-01
影响因子：
15.9
通讯作者：
Shadel, Gerald S.
中科院分区：
文献类型：
--
作者：
Eaton, Jana S.;Lin, Z. Ping;Shadel, Gerald S.
共济失调-远端扩张症突变(ATM)激酶协调核DNA损伤反应，但被认为参与其他重要和临床相关的功能。在这里，我们提供了我们认为ATM的两个新的和相互交织的作用的证据：调节核糖核苷酸还原酶(RR)，脱氧核糖核苷三磷酸从头合成的限速酶，以及控制线粒体的稳态。在正常生长条件下，共济失调-毛细血管扩张症(A-T)患者成纤维细胞、用ATM抑制剂KU55933处理的野生型成纤维细胞以及RR被药物或RNA干扰(RNAi)抑制的细胞都会导致线粒体DNA(MtDNA)耗尽。在原代A-T成纤维细胞中，ATM信号的中断还导致RR的R1、R2和p53R2亚基的全球失调，电离辐射导致依赖RR的mtDNA上调，高线粒体转录因子A(MtTFA)/mtDNA比率，以及对线粒体呼吸和翻译抑制剂的抵抗力增加。最后，在ATM缺失的小鼠组织中，RR的R1亚单位的表达减少，mtDNA拷贝数出现组织特异性的变化，后者在人类A-T患者的组织中重现。基于这些结果，我们认为RR和线粒体动态平衡的破坏是导致A-T复杂病理的原因，RR基因是mtDNA耗竭综合征的候选致病基因。
Ataxia-telarigiectasia mutated (ATM) kinase orchestrates nuclear DNA damage responses but is proposed to be involved in other important and clinically relevant functions. Here, we provide evidence for what we believe are 2 novel and intertwined roles for ATM: the regulation of ribonucleotide reductase (RR), the rate-limiting enzyme in the de novo synthesis of deoxyribonucleoside triphosphates, and control of mitochondrial homeostasis. Ataxia-telangiectasia (A-T) patient fibroblasts, wild-type fibroblasts treated with the ATM inhibitor KU55933, and cells in which RR is inhibited pharmacologically or by RNA interference (RNAi) each lead to mitochondrial DNA (mtDNA) depletion under normal growth conditions. Disruption of ATM signaling in primary A-T fibroblasts also leads to global dysregulation of the R1, R2, and p53R2 subunits of RR, abrogation of RR-dependent upregulation of mtDNA in response to ionizing radiation, high mitochondrial transcription factor A (mtTFA)/mtDNA ratios, and increased resistance to inhibitors of mitochondrial respiration and translation. Finally, there are reduced expression of the R1 subunit of RR and tissue-specific alterations of mtDNA copy number in ATM null mouse tissues, the latter being recapitulated in tissues from human A-T patients. Based on these results, we propose that disruption of RR and mitochondrial homeostasis contributes to the complex pathology of A-T and that RR genes are candidate disease loci in mtDNA-depletion syndromes.