Site-specific DICER and DROSHA RNA products control the DNA-damage response.
Site-specific DICER and DROSHA RNA products control the DNA-damage response.
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DOI：
10.1038/nature11179
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发表时间：
2012-08-09
期刊：
影响因子：
64.8
通讯作者：
di Fagagna, Fabrizio d'Adda
中科院分区：
文献类型：
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作者：
Francia, Sofia;Michelini, Flavia;Saxena, Alka;Tang, Dave;de Hoon, Michiel;Anelli, Viviana;Mione, Marina;Carninci, Piero;di Fagagna, Fabrizio d'Adda
非编码RNA(NcRNA)参与了越来越多的细胞事件。一些ncRNAs被Disher和DROSHA核糖核酸酶处理，产生参与RNA干扰(RNAi)的小双链RNAs。DNA损伤反应(DDR)是一种起源于DNA损伤并阻止细胞增殖的信号通路。到目前为止，还没有DICER或DROSHA RNA产品控制DDR激活的报道。在这里，我们证明了在癌基因诱导的遗传毒性应激和外源DNA损伤时，DICER和DROSHA是激活DDR所必需的，但不是RNAi途径的下游元件，这一点也通过哺乳动物细胞和斑马鱼中DDR焦点的形成和检查点分析进行了研究。DDR灶对RNaseA处理敏感，需要依赖于DICER和DROSHA的RNA产品来恢复处理细胞中的DDR灶。通过RNA深度测序和对DDR在可诱导的唯一DNA双链断裂(DSB)上的激活的研究，我们证明了DDR焦点的形成需要依赖于DICER和DROSHA位点的小RNA，称为DDRNAs，它们以Mre11-Rad50-NBS1(MRN)复合体依赖的方式发挥作用。化学合成或体外生成的DDRNAs，在没有其他细胞RNA的情况下，也足以恢复RNaseA处理的细胞中的DDR。我们的结果描述了一类新的ncRNAs在控制DNA损伤部位的DDR激活方面的一个意想不到的直接作用。
Non-coding RNAs (ncRNAs) are involved in an increasing number of cellular events. Some ncRNAs are processed by DICER and DROSHA ribonucleases to give rise to small double-stranded RNAs involved in RNA interference (RNAi). The DNA-damage response (DDR) is a signaling pathway that originates from the DNA lesion and arrests cell proliferation. So far, DICER or DROSHA RNA products have not been reported to control DDR activation. Here we show that DICER and DROSHA, but not downstream elements of the RNAi pathway, are necessary to activate DDR upon oncogene-induced genotoxic stress and exogenous DNA damage, as studied also by DDR foci formation in mammalian cells and zebrafish and by checkpoint assays. DDR foci are sensitive to RNase A treatment, and DICER- and DROSHA-dependent RNA products are required to restore DDR foci in treated cells. Through RNA deep sequencing and studies of DDR activation at an inducible unique DNA double-strand break (DSB), we demonstrate that DDR foci formation requires site-specific DICER- and DROSHA-dependent small RNAs, named DDRNAs, which act in a MRE11-RAD50-NBS1 (MRN) complex-dependent manner. Chemically synthesized or in vitro-generated by DICER cleavage, DDRNAs are sufficient to restore DDR in RNase A-treated cells, also in the absence of other cellular RNAs. Our results describe an unanticipated direct role of a novel class of ncRNAs in the control of DDR activation at sites of DNA damage.
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影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
14.8
作者：
Dupre, Aude;Boyer-Chatenet, Louise;Gautier, Jean
通讯作者：
Gautier, Jean
影响因子：
4
作者：
Pryde, F;Khalili, S;Adachi, Y
通讯作者：
Adachi, Y
影响因子：
64.5
作者：
Narita, M;Nunez, S;Lowe, SW
通讯作者：
Lowe, SW
DOI：
10.1038/nrm3047
发表时间：
2011-02
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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