Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell–induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.

神经元是我们体内寿命最长的细胞，缺乏 DNA 复制，这使得它们依赖于有限的 DNA 修复机制来维持基因组保真度。这些修复机制随着年龄的增长而下降，但我们对基因组不稳定性如何出现以及神经元和其他长寿细胞可能进化出哪些策略以在人类寿命期间保护其基因组知之甚少。人类胚胎干细胞诱导神经元的靶向测序方法表明，在神经元中，DNA 修复在保护必需基因的明确定义的热点处得到丰富。这些热点富含组蛋白 H2A 亚型和 RNA 结合蛋白，并且与人类基因组的进化保守元素相关。