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Nature Neuroscience:一种DNA修复酶可修复特定基因组不稳定性

来源:Nature Neuroscience 2013-08-30 09:11

去乙酰化酶1(SIRT1)是一种用来修复受损DNA的酶,但8月《自然—神经科学》上的一项报告发现,该酶还可以修复患有神经退行性疾病诸如阿尔兹海默症和肌萎缩侧索硬化症(又名“渐冻人”症,ALS)的小鼠体内的基因组不稳定性。

与身体中其他细胞不同,成年哺乳动物大脑中的神经元不会发生分裂。既然不能通过复制现有DNA来实现修复,那么DNA受损以及导致的基因组不稳定对神经元来说是一件特别麻烦的事。而且,DNA分子链的物理断裂与衰老和神经退行性疾病比如阿尔兹海默症和ALS患病情况下的认知下降也存在着联系。

因为人们已经知道去乙酰化酶可以防止大脑细胞凋亡,Li-Huei Tsai等人便研究了这种保护行为的分子机制。他们发现,没有SIRT1,神经元无法修复由有毒化学物质造成的DNA损伤。此外,他们还发现SIRT1的行为受到另一种酶的控制调节——这种酶负责将DNA包裹进行压缩。该研究认为利用SIRT1激活药物治疗患有神经退行性疾病和阿尔兹海默症的小鼠的方法也能防止神经元发生DNA损伤。(生物谷 Bioon.com)

生物谷推荐的英文摘要

IRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons

Matthew M Dobbin,1, 2, 3, 9 Ram Madabhushi,1, 2, 3, 9 Ling Pan,1, 2, 3 Yue Chen,4, 5 Dohoon Kim,6 Jun Gao,1, 2, 3, 8 Biafra Ahanonu,1, 2, 3 Ping-Chieh Pao,1, 2, 3 Yi Qiu,7 Yingming Zhao4, 5 & Li-Huei Tsai1, 2, 3

Nature Neuroscience doi:10.1038/nn.3460

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. We sought to characterize the roles of the NAD+-dependent deacetylase SIRT1 in the neuronal response to DNA double-strand breaks (DSBs). We found that SIRT1 was rapidly recruited to DSBs in postmitotic neurons, where it showed a synergistic relationship with ataxia telangiectasia mutated (ATM). SIRT1 recruitment to breaks was ATM dependent; however, SIRT1 also stimulated ATM autophosphorylation and activity and stabilized ATM at DSB sites. After DSB induction, SIRT1 also bound the neuroprotective class I histone deacetylase HDAC1. We found that SIRT1 deacetylated HDAC1 and stimulated its enzymatic activity, which was necessary for DSB repair through the nonhomologous end-joining pathway. HDAC1 mutations that mimic a constitutively acetylated state rendered neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promoted HDAC1 deacetylation also reduced 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.

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