同济大学毛志勇教授发表Cell Death & Differentiation文章

　　

     基因组稳定性下降是生物体衰老发生极其重要的一个标志。细胞长期在各种因素的影响下，DNA遭受着多种损伤，若这些损伤不被及时准确地修复将诱发基因组稳定性的下降，进而影响细胞的正常生命活动。这些损伤中，DNA双链断裂（DSBs）是最为严重的基因组损伤之一。近年来，虽然关于DNA DSBs修复与衰老发生的研究有很多，但大部分集中在啮齿类动物。而由于样本的稀缺及检测手段的限制，人类衰老相关DNA修复的研究受到很大的限制。

       来自同济大学生命科学与技术学院的研究人员利用从上海长征医院获得的不同年龄段的50株女性眼睑皮肤组织，从中分离并建立了成纤维细胞系，并借助其课题组独特的检测DNA DSB修复两条通路－非同源末端连接修复（NHEJ）和同源重组修复（HR）－效率的报告载体，发现随着年龄的增长细胞的DNA修复能力和基因组稳定性下调，导致年老组织分离的细胞对诱发双链断裂发生的电离辐射敏感性上升。后续分子机制研究表明，XRCC4、Lig4和Lig3蛋白水平的下调引起NHEJ修复效率和精确性的下降，而HR修复通路中的关键性因子Rad51招募至损伤处能力的下调则导致了HR修复效率的下降。而通过过量表达XRCC4和Lig4重新激活NHEJ通路后，则可以抑制胁迫性诱导细胞早衰的发生。

       中国已经进入老龄化社会，该研究为今后发展靶向DNA双链断裂修复提高基因组稳定性进而延缓衰老的方法奠定了理论基础。该研究于2016年7月8日发表于Cell Death & Differentiation杂志。

        本研究在毛志勇教授的指导下，由博士研究生李珍、博士后张文俊、本科生陈御和郭文瑄等人共同完成。本课题获得了国家科技部、国家自然科学基金委、中组部“青年****”以及上海市“浦江人才计划”等项目的资助。

原文摘要：

Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans

Failing to repair DNA double-strand breaks by either nonhomologous end joining (NHEJ) or homologous recombination (HR) poses a threat to genome integrity, and may have roles in the onset of aging and age-related diseases. Recent work indicates an age-related decrease of NHEJ efficiency in mouse models, but whether NHEJ and HR change with age in humans and the underlying mechanisms of such a change remain uncharacterized. Here, using 50 eyelid fibroblast cell lines isolated from healthy donors at the age of 16–75 years, we demonstrate that the efficiency and fidelity of NHEJ, and the efficiency of HR decline with age, leading to increased IR sensitivity in cells isolated from old donors. Mechanistic analysis suggests that decreased expression of XRCC4, Lig4 and Lig3 drives the observed, age-associated decline of NHEJ efficiency and fidelity. Restoration of XRCC4 and Lig4 significantly promotes the fidelity and efficiency of NHEJ in aged fibroblasts. In contrast, essential HR-related factors, such as Rad51, do not change in expression level with age, but Rad51 exhibits a slow kinetics of recruitment to DNA damage sites in aged fibroblasts. Further rescue experiments indicate that restoration of XRCC4 and Lig4 may suppress the onset of stress-induced premature cellular senescence, suggesting that improving NHEJ efficiency and fidelity by targeting the NHEJ pathway holds great potential to delay aging and mitigate aging-related pathologies.