Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK.
National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
Nat Genet. 2022 Feb;54(2):115-120. doi: 10.1038/s41588-021-01001-y. Epub 2022 Feb 10.
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.
神经元基因组对 DNA 修复的缺失或减弱特别敏感，当 DNA 修复受损时，许多神经疾病就会随之而来。众所周知，神经元基因组会受到随机的 DNA 损伤，这很可能是由于大脑中广泛的氧化应激。然而，最近的研究已经确定了神经元中存在意外的高水平“程序性”DNA 断裂，我们提出这些断裂是在神经元发育、分化和维持过程中固有的生理 DNA 代谢过程中产生的。迄今为止，程序性 DNA 断裂在正常神经元生理学和疾病中的作用仍然相对未知。然而，对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，这些特征在基因组的调控区域富集。在这里，我们探索了一种神经元中 DNA 修复的范例，在这种范例中，基因组受到了正常神经元功能中固有程序性基因组断裂的错误影响的保护。
