DNA end joining becomes less efficient and more error-prone during cellular senescence
DNA end joining becomes less efficient and more error-prone during cellular senescence
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DOI：
10.1073/pnas.0400726101
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发表时间：
2004-05-18
影响因子：
11.1
通讯作者：
Gorbunova, V
中科院分区：
文献类型：
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作者：
Seluanov, A;Mittelman, D;Gorbunova, V
体细胞突变的积累被认为有助于衰老过程。基因组不稳定性已被证明在衰老过程中增加，这表明DNA双链断裂（DSB）修复功能异常。令人惊讶的是，DSB修复还没有被检查关于细胞衰老。因此，我们研究了年轻的，衰老的，和衰老的正常人成纤维细胞修复DSB转染DNA的能力，通过使用荧光报告底物。我们已经发现，相对于年轻细胞，在早老和衰老细胞中末端连接的效率降低高达4.5倍。末端连接的序列分析表明，精确连接的频率较高，在年轻的细胞，而在老细胞的末端连接与扩展缺失。这些结果表明，在细胞衰老过程中，末端连接变得低效且更容易出错。此外，在衰老细胞中使用微同源性进行末端连接的能力受到损害，这表明年轻细胞和衰老细胞可能使用不同的末端连接途径。我们推测，低效率和异常的末端连接可能是老年人与年龄相关的基因组不稳定性和癌症发病率较高的潜在机制。
Accumulation of somatic mutations is thought to contribute to the aging process. Genomic instability has been shown to increase during aging, suggesting an aberrant function of DNA doublestrand break (DSB) repair. Surprisingly, DSB repair has not been examined with respect to cellular senescence. Therefore, we have studied the ability of young, presenescent, and senescent normal human fibroblasts to repair DSBs in transfected DNA by using a fluorescent reporter substrate. We have found that the efficiency of end joining is reduced up to 4.5 fold in presenescent and senescent cells, relative to young cells. Sequence analysis of end junctions showed that the frequency of precise ligation was higher in young cells, whereas end joining in old cells was associated with extended deletions. These results indicate that end joining becomes inefficient and more error-prone during cellular senescence. Furthermore, the ability to use microhomologies for end joining was compromised in senescent cells, suggesting that young and senescent cells may use different end joining pathways. We hypothesize that inefficient and aberrant end joining is a likely mechanism underlying the age-related genomic instability and higher incidence of cancer in the elderly.