MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response
MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response
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DOI：
10.1038/emboj.2009.156
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发表时间：
2009-07-22
期刊：
影响因子：
11.4
通讯作者：
Persengiev, Stephan P.
中科院分区：
文献类型：
--
作者：
Pothof, Joris;Verkaik, Nicole S.;Persengiev, Stephan P.
DNA 损伤引发 DNA 修复、细胞周期调节和细胞凋亡。这种 DNA 损伤反应包括转录和翻译后水平的基因表达调控。我们发现细胞对紫外线诱导的 DNA 损伤的反应也在转录后水平受到 microRNA 的调节。通过敲除 microRNA 加工途径的重要组成部分（Dicer 和 Ago2），microRNA 介导的基因沉默抑制严重降低了紫外线损伤后的生存和检查点反应。紫外线损伤引发了细胞周期依赖性的 Ago2 重新定位为应激颗粒和各种 microRNA 表达变化。 Ago2 重定位需要 CDK 活性，但独立于 ATM/ATR 检查点信号传导，而 UV 响应性 microRNA 表达仅部分独立于 ATM/ATR。 microRNA 表达变化和应激颗粒形成在基因毒性应激后的最初几个小时内最为明显，表明 microRNA 介导的基因调控比大多数转录反应更早起作用。紫外线诱导的 miR-16 下调检查点基因 CDC25a 并调节细胞增殖，说明了 microRNA 反应的功能。我们得出的结论是，microRNA 介导的基因调控为 DNA 损伤反应增加了一个新的维度。 EMBO 杂志 (2009) 28, 2090-2099。 doi：10.1038/emboj.2009.156； 2009 年 6 月 18 日在线发布
DNA damage provokes DNA repair, cell-cycle regulation and apoptosis. This DNA-damage response encompasses gene-expression regulation at the transcriptional and post-translational levels. We show that cellular responses to UV-induced DNA damage are also regulated at the post-transcriptional level by microRNAs. Survival and checkpoint response after UV damage was severely reduced on microRNA-mediated gene-silencing inhibition by knocking down essential components of the microRNA-processing pathway (Dicer and Ago2). UV damage triggered a cell-cycle-dependent relocalization of Ago2 into stress granules and various microRNA-expression changes. Ago2 relocalization required CDK activity, but was independent of ATM/ATR checkpoint signalling, whereas UV-responsive microRNA expression was only partially ATM/ATR independent. Both microRNA-expression changes and stress-granule formation were most pronounced within the first hours after genotoxic stress, suggesting that microRNA-mediated gene regulation operates earlier than most transcriptional responses. The functionality of the microRNA response is illustrated by the UV-inducible miR-16 that downregulates checkpoint-gene CDC25a and regulates cell proliferation. We conclude that microRNA-mediated gene regulation adds a new dimension to the DNA-damage response. The EMBO Journal (2009) 28, 2090-2099. doi: 10.1038/emboj.2009.156; Published online 18 June 2009