The threat of programmed DNA damage to neuronal genome integrity and plasticity
The threat of programmed DNA damage to neuronal genome integrity and plasticity
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DOI：
10.1038/s41588-021-01001-y
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发表时间：
2022-02-10
期刊：
影响因子：
30.8
通讯作者：
Nussenzweig, Andre
中科院分区：
文献类型：
--
作者：
Caldecott, Keith W.;Ward, Michael E.;Nussenzweig, Andre
神经元基因组对DNA修复的丢失或减弱特别敏感，当DNA修复受损时，许多神经系统疾病随之而来。众所周知，神经元基因组受到随机DNA损伤，很可能是因为大脑中广泛的氧化应激。然而，最近的研究发现，神经元中出现了意想不到的高水平的程序性DNA断裂，我们认为这种断裂发生在神经元发育、分化和维持所固有的生理DNA代谢过程中。到目前为止，程序性DNA断裂在正常神经生理学和疾病中的作用仍然相对未知。然而，神经退行性疾病的批量和单细胞测序分析揭示了与年龄相关的体细胞突变特征，这些特征丰富在基因组的调节区。在这里，我们探索了一种神经元DNA修复的范例，在这种范式中，基因组受到保护，不受正常神经元功能固有的程序性基因组断裂的错误影响。正常的细胞过程可以导致DNA断裂，而DNA断裂成为细胞DNA修复机制的底物。聚焦于神经元，这篇透视文章探索了这种“程序化的”DNA损伤及其修复在健康、衰老和神经退行性疾病中的作用。
The neuronal genome is particularly sensitive to loss or attenuation of DNA repair, and many neurological diseases ensue when DNA repair is impaired. It is well-established that the neuronal genome is subjected to stochastic DNA damage, most likely because of extensive oxidative stress in the brain. However, recent studies have identified unexpected high levels of 'programmed' DNA breakage in neurons, which we propose arise during physiological DNA metabolic processes intrinsic to neuronal development, differentiation and maintenance. The role of programmed DNA breaks in normal neuronal physiology and disease remains relatively unexplored thus far. However, bulk and single-cell sequencing analyses of neurodegenerative diseases have revealed age-related somatic mutational signatures that are enriched in regulatory regions of the genome. Here, we explore a paradigm of DNA repair in neurons, in which the genome is safeguarded from erroneous impacts of programmed genome breakage intrinsic to normal neuronal function.Normal cellular processes can cause DNA breaks which become substrates for the cell's DNA repair machinery. Focusing on neurons, this Perspective article explores the role of this 'programmed' DNA damage and its repair in health, ageing and neurodegenerative disease.