Transcriptional repression of DNA repair genes is a hallmark and a cause of cellular senescence.
Transcriptional repression of DNA repair genes is a hallmark and a cause of cellular senescence.
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DOI：
10.1038/s41419-018-0300-z
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发表时间：
2018-02-15
影响因子：
9
通讯作者：
Bernard D
中科院分区：
文献类型：
--
作者：
Collin G;Huna A;Warnier M;Flaman JM;Bernard D
细胞衰老反应（i）由许多应激激活，（ii）以稳定的增殖停滞为特征，以及（iii）以一组特定特征为特征。及时调节衰老被认为是有益的，而慢性衰老，如在正常或过早老化是有害的，因为它有利于大多数，如果不是所有，与年龄有关的疾病。在这项研究中，使用内部或公开可用的微阵列分析衰老细胞的转录组，以及通过RT-qPCR和免疫印迹分析几个DNA修复基因的表达水平，我们表明，抑制DNA修复基因的表达与细胞衰老。这种抑制是由RB/E2 F途径介导的，并且它可能在衰老诱导中起因果作用，因为通过siRNA的单个DNA修复基因抑制诱导了早衰的特征。重要的是，独立于直接DNA损伤激活RB也导致DNA修复基因的抑制和随后的DNA损伤和衰老的诱导。其原理是，细胞衰老过程中观察到的DNA损伤是由遗传毒性攻击（UV、IR和ROS）后的DNA损伤或致癌激活后的复制应激诱导直接引起的。我们的体外研究结果支持了在大多数（如果不是所有的话）细胞衰老中观察到的DNA损伤的诱导和积累中DNA修复基因表达的缺失的一个很大程度上未被怀疑的贡献，从而在细胞衰老的诱导中。使用体内模型的进一步证明将有助于推广我们的研究结果。
Cellular senescence response is (i) activated by numerous stresses, (ii) is characterized by a stable proliferation arrest, and (iii) by a set of specific features. Timely regulated senescence is thought to be beneficial, whereas chronic senescence such as during normal or premature aging is deleterious as it favors most, if not all, age-related diseases. In this study, using in-house or publicly available microarray analyses of transcriptomes of senescent cells, as well as analyses of the level of expression of several DNA repair genes by RT-qPCR and immunoblot, we show that repression of DNA repair gene expression is associated with cellular senescence. This repression is mediated by the RB/E2F pathway and it may play a causal role in senescence induction, as single DNA repair gene repression by siRNA induced features of premature senescence. Importantly, activating RB independently of direct DNA damage also results in repression of DNA repair genes and in the subsequent induction of DNA damage and senescence. The dogma is that DNA damage observed during cellular senescence is directly provoked by DNA lesions following genotoxic attack (UV, IR, and ROS) or by induction of replicative stress upon oncogenic activation. Our in vitro results support a largely unsuspected contribution of the loss of DNA repair gene expression in the induction and the accumulation of the DNA damage observed in most, if not all, kinds of cellular senescence, and thus in the induction of cellular senescence. Further demonstration using in vivo models will help to generalize our findings.
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