Defective DNA repair increases susceptibility to senescence through extension of Chk1-mediated G2 checkpoint activation.
Defective DNA repair increases susceptibility to senescence through extension of Chk1-mediated G2 checkpoint activation.
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DOI：
10.1038/srep31194
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发表时间：
2016-08-10
影响因子：
4.6
通讯作者：
Nakanishi M
中科院分区：
文献类型：
--
作者：
Johmura Y;Yamashita E;Shimada M;Nakanishi K;Nakanishi M
DNA修复缺陷导致的衰老易感性是孕激素综合征患者的一个主要特征，但DNA修复缺陷如何导致衰老的分子机制在很大程度上尚不清楚。我们在这里证明，抑制DNA修复通路延长了依赖Chk1的G2检查点激活的持续时间，并通过增强有丝分裂跳过使细胞对衰老敏感。通过引入TopBP1激活域和不可降解的Claspin突变体来延长G2检查点的激活，使细胞对衰老敏感。相反，通过表达SIRT6或耗尽OTUB2而缩短G2检查点激活可以降低衰老的易感性。来自孕期综合征的成纤维细胞测试表明，G2检查点激活的延长与衰老易感性的增加之间存在相关性。这些结果表明，DNA修复缺陷导致的G2检查点激活延长是早孕综合征患者衰老易感性的关键。
Susceptibility to senescence caused by defective DNA repair is a major hallmark of progeroid syndrome patients, but molecular mechanisms of how defective DNA repair predisposes to senescence are largely unknown. We demonstrate here that suppression of DNA repair pathways extends the duration of Chk1-dependent G2 checkpoint activation and sensitizes cells to senescence through enhancement of mitosis skipping. Extension of G2 checkpoint activation by introduction of the TopBP1 activation domain and the nondegradable mutant of Claspin sensitizes cells to senescence. In contrast, a shortening of G2 checkpoint activation by expression of SIRT6 or depletion of OTUB2 reduces susceptibility to senescence. Fibroblasts from progeroid syndromes tested shows a correlation between an extension of G2 checkpoint activation and an increase in the susceptibility to senescence. These results suggest that extension of G2 checkpoint activation caused by defective DNA repair is critical for senescence predisposition in progeroid syndrome patients.