High fidelity of genetic transmission in neural stem and progenitor cells (NSPCs) has been long time considered to be crucial for brain development and homeostasis. However, recent studies have identified recurrent DSB clusters in dividing NSPCs, which may underlie the diversity of neuronal cell types. This raised the interest in understanding how NSPCs sense and repair DSBs and how this mechanism could be altered by environmental genotoxic stress caused by pollutants or ionizing radiation. Here, we show that embryonic mouse neural stem and progenitor cells (NSPCs) have significantly higher capacity than mouse embryonic fibroblasts (MEFs) to maintain their chromosome stability in response to acute (γ-radiation) and chronic (tritiated thymidine -3H-T- incorporation into DNA) genotoxic stress. Cells deficient for XLF/Cernunnos, which is involved in non-homologous end joining DNA (NHEJ) repair, highlighted important variations in fidelity of DNA repair pathways between the two cell types. Strikingly, a progressive and generalized chromosome instability was observed in MEFs cultured with 3H-T at long-term, whereas NSPCs cultured in the same conditions, preserved their chromosome stability thanks to higher DNA repair activity further enhanced by an adaptive response and also to the elimination of damaged cells by apoptosis. This specific DNA damage response of NSPCs may rely on the necessity for preservation of their genome stability together with their possible function in creating neuronal genetic diversity.

中文翻译：

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响应急性或慢性遗传毒性应激，胚胎神经干细胞和祖细胞的染色体稳定性高于成纤维细胞。

长期以来，人们一直认为神经干细胞和祖细胞（NSPC）中遗传传递的高保真度对于大脑发育和体内平衡至关重要。但是，最近的研究已经确定了分裂的NSPC中的复发性DSB簇，这可能是神经元细胞类型多样性的基础。这引起了人们对了解NSPC如何感测和修复DSB以及如何通过污染物或电离辐射引起的环境遗传毒性应力如何改变这种机制的兴趣。在这里，我们表明，胚胎小鼠神经干细胞和祖细胞（NSPC）具有显着高于小鼠胚胎成纤维细胞（MEF）的能力，以响应急性（γ-射线）和慢性（chronic化胸苷-3H-T-掺入DNA）的遗传毒性胁迫。XLF / Cernunnos缺乏的细胞，参与非同源末端连接DNA（NHEJ）修复的研究突显了两种细胞类型之间DNA修复途径保真度的重要变化。令人惊讶的是，在长期用3H-T培养的MEF中观察到了渐进性和普遍的染色体不稳定性，而在相同条件下培养的NSPC由于更高的DNA修复活性被适应性反应进一步增强，并且对通过凋亡消除受损细胞。NSPC的这种特定的DNA损伤反应可能依赖于保持其基因组稳定性以及其在创建神经元遗传多样性中的可能功能的必要性。在长期用3H-T培养的MEF中观察到渐进性和普遍的染色体不稳定性，而在相同条件下培养的NSPC在较高的DNA修复活性下可通过适应性反应进一步增强，并且消除了通过凋亡破坏细胞。NSPC的这种特定的DNA损伤反应可能依赖于保持其基因组稳定性以及其在创建神经元遗传多样性中的可能功能的必要性。在长期用3H-T培养的MEF中观察到渐进性和普遍的染色体不稳定性，而在相同条件下培养的NSPC在较高的DNA修复活性下可通过适应性反应进一步增强，并且消除了通过凋亡破坏细胞。NSPC的这种特定的DNA损伤反应可能依赖于保持其基因组稳定性以及其在创建神经元遗传多样性中的可能功能的必要性。