Base excision repair but not DNA double-strand break repair is impaired in aged human adipose-derived stem cells
Base excision repair but not DNA double-strand break repair is impaired in aged human adipose-derived stem cells
复制标题
衰老的人类脂肪干细胞中碱基切除修复受损，但 DNA 双链断裂修复并未受损
DOI：
10.1111/acel.13062
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发表时间：
2020
期刊：
影响因子：
7.8
通讯作者：
Mao Zhiyong
中科院分区：
文献类型：
--
作者：
Zhang Haiping;Cai Bailian;Geng Anke;Tang Huanyin;Zhang Wenjun;Li Sheng;Jiang Ying;Tan Rong;Wan Xiaoping;Mao Zhiyong
DNA修复能力的下降导致不同物种体细胞中与年龄相关的基因组完整性下降。然而，由于缺乏临床样本和适当的工具来研究DNA修复，DNA修复中与年龄相关的变化是否以及如何导致人类成体干细胞基因组完整性的丧失仍然没有完全表征。在这里，我们从健康个体中分离出20个眼睑脂肪来源的干细胞（ADSC）系（年轻：10个供体，年龄范围为17-25岁;老年：10个供体，年龄范围为50-59岁）。使用这些细胞系，我们系统地比较了年轻组和老年组之间的碱基切除修复（BER）和两种DNA双链断裂（DSB）修复途径-非同源末端连接（NHEJ）和同源重组（HR）的效率。令人惊讶的是，我们发现BER而不是NHEJ或HR的效率在老年人ADSC中受损，这与先前发现的人成纤维细胞中DSB修复随着年龄的增长而下降相反。我们还证明BER效率与尾矩呈负相关，这反映了人类ADSC中基因组完整性的丧失。机制研究表明，在蛋白质水平上，XRCC 1（而不是其他BER因子）表现出与年龄相关的下降。XRCC 1的过表达逆转了BER效率和基因组完整性的下降，表明XRCC 1是稳定老化ADSC基因组的潜在治疗靶点。
The decline in DNA repair capacity contributes to the age‐associated decrease in genome integrity in somatic cells of different species. However, due to the lack of clinical samples and appropriate tools for studying DNA repair, whether and how age‐associated changes in DNA repair result in a loss of genome integrity of human adult stem cells remains incompletely characterized. Here, we isolated 20 eyelid adipose‐derived stem cell (ADSC) lines from healthy individuals (young: 10 donors with ages ranging 17–25 years; old: 10 donors with ages ranging 50–59 years). Using these cell lines, we systematically compared the efficiency of base excision repair (BER) and two DNA double‐strand break (DSB) repair pathways—nonhomologous end joining (NHEJ) and homologous recombination (HR)—between the young and old groups. Surprisingly, we found that the efficiency of BER but not NHEJ or HR is impaired in aged human ADSCs, which is in contrast to previous findings that DSB repair declines with age in human fibroblasts. We also demonstrated that BER efficiency is negatively associated with tail moment, which reflects a loss of genome integrity in human ADSCs. Mechanistic studies indicated that at the protein level XRCC1, but not other BER factors, exhibited age‐associated decline. Overexpression of XRCC1 reversed the decline of BER efficiency and genome integrity, indicating that XRCC1 is a potential therapeutic target for stabilizing genomes in aged ADSCs.