ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair.
ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair.
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DOI：
10.1038/emboj.2010.330
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发表时间：
2011-02-02
期刊：
影响因子：
11.4
通讯作者：
Costanzo, Vincenzo
中科院分区：
文献类型：
--
作者：
Cosentino, Claudia;Grieco, Domenico;Costanzo, Vincenzo
DNA损伤诱导的ATM激酶与代谢性磷酸戊糖途径相关，从而促进DNA修复所需的核苷酸前体的生物合成并刺激抗氧化剂NADPH的产生，这可以解释缺乏ATM功能的共济失调毛细血管扩张症患者的神经缺陷。共济失调性毛细血管扩张症（Ataxia telangiectasia，A-T）是由ATM缺陷引起的人类疾病，其特征在于放射敏感性、癌症、不育、免疫缺陷和神经缺陷等症状。ATM控制细胞周期的几个方面，并促进双链断裂（DSB）的修复。这可能是大多数A-T临床表现的原因。然而，受损的反应活性氧（ROS）也可能有助于A-T的发病机制。在这里，我们表明，ATM通过调节磷酸戊糖途径（PPP）促进抗氧化反应。ATM激活诱导葡萄糖-6-磷酸脱氢酶（G6 PD）活性，这是PPP的限制酶，负责产生NADPH，一种必需的抗氧化辅助因子。ATM促进Hsp 27磷酸化并与G6 PD结合，刺激其活性。我们还表明，ATM依赖性PPP刺激增加核苷酸生产和G6 PD缺陷细胞受损的DSB修复。这些数据表明，ATM通过刺激NADPH的产生和促进DSB修复所需的核苷酸的合成来保护细胞免受ROS积累。
The DNA damage-induced ATM kinase is linked to the metabolic pentose phosphate pathway, thus boosting biosynthesis of nucleotide precursors required for DNA repair and stimulating generation of the anti-oxidant NADPH, which may explain neurological defects of ataxia telangiectasia patients lacking ATM function. Ataxia telangiectasia (A-T) is a human disease caused by ATM deficiency characterized among other symptoms by radiosensitivity, cancer, sterility, immunodeficiency and neurological defects. ATM controls several aspects of cell cycle and promotes repair of double strand breaks (DSBs). This probably accounts for most of A-T clinical manifestations. However, an impaired response to reactive oxygen species (ROS) might also contribute to A-T pathogenesis. Here, we show that ATM promotes an anti-oxidant response by regulating the pentose phosphate pathway (PPP). ATM activation induces glucose-6-phosphate dehydrogenase (G6PD) activity, the limiting enzyme of the PPP responsible for the production of NADPH, an essential anti-oxidant cofactor. ATM promotes Hsp27 phosphorylation and binding to G6PD, stimulating its activity. We also show that ATM-dependent PPP stimulation increases nucleotide production and that G6PD-deficient cells are impaired for DSB repair. These data suggest that ATM protects cells from ROS accumulation by stimulating NADPH production and promoting the synthesis of nucleotides required for the repair of DSBs.
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DOI：
10.1016/j.bbapap.2008.11.010
发表时间：
2009-03-01
影响因子：
3.2
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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