SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons.
SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons.
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DOI：
10.1038/nn.3460
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发表时间：
2013-08
影响因子：
25
通讯作者：
Tsai LH
中科院分区：
文献类型：
--
作者：
Dobbin MM;Madabhushi R;Pan L;Chen Y;Kim D;Gao J;Ahanonu B;Pao PC;Qiu Y;Zhao Y;Tsai LH
DNA修复缺陷与随着年龄增长认知能力下降和神经退行性疾病有关。然而，保护神经元免受基因毒性应激的机制在很大程度上仍不清楚。在本报告中，我们描述了NAD+依赖的去乙酰化酶SIRT1在神经元对DNA双链断裂（DSBs）的反应中的作用。我们发现SIRT1被迅速招募到有丝分裂后神经元的dsb，在那里它与ATM表现出协同关系。SIRT1对休息的吸收依赖于atm；然而，SIRT1也刺激ATM的自磷酸化和活性，并在DSB位点稳定ATM。在DSB诱导下，SIRT1还结合神经保护I类组蛋白去乙酰化酶HDAC1。我们发现SIRT1使HDAC1去乙酰化并刺激其酶活性，这是通过非同源末端连接（NHEJ）途径修复DSB所必需的。模拟组成性乙酰化状态的HDAC1突变体使神经元更容易受到DNA损伤，而在两种神经变性小鼠模型中，促进HDAC1去乙酰化的药理学SIRT1激活剂也能减少DNA损伤。我们认为SIRT1是DSB反应的一个顶端传感器，SIRT1的激活为神经变性提供了一个重要的治疗途径。
Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease. Yet the mechanisms that protect neurons from genotoxic stress remain largely obscure. In this report, we characterize the roles of the NAD+-dependent deacetylase, SIRT1, in the neuronal response to DNA double-strand breaks (DSBs). We show that SIRT1 is rapidly recruited to DSBs in postmitotic neurons, where it exhibits a synergistic relationship with ATM. SIRT1 recruitment to breaks is ATM-dependent; however, SIRT1 also stimulates ATM auto-phosphorylation and activity and stabilizes ATM at DSB sites. Upon DSB induction, SIRT1 also binds the neuroprotective class I histone deacetylase, HDAC1. We show that SIRT1 deacetylates HDAC1 and stimulates its enzymatic activity, which is necessary for DSB repair through the nonhomologous end-joining (NHEJ) pathway. HDAC1 mutants that mimic a constitutively acetylated state render neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promote HDAC1 deacetylation also reduce DNA damage in two mouse models of neurodegeneration. We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration.