德罗沙
掷骰子
核糖核酸
核糖核酸酶Ⅲ
细胞生物学
DNA损伤
生物
核糖核酸酶P
核糖核酸酶H
非编码RNA
分子生物学
RNA干扰
DNA
小RNA
化学
遗传学
基因
作者
Sofia Francia,Flavia Michelini,Alka Saxena,Dave Tang,Myung Hoon,Viviana Anelli,Marina Mione,Piero Carninci,Fabrizio d’Adda di Fagagna
出处
期刊:Nature
[Springer Nature]
日期:2012-05-23
卷期号:488 (7410): 231-235
被引量:467
摘要
Non-coding RNAs (ncRNAs) are involved in an increasingly recognized number of cellular events. Some ncRNAs are processed by DICER and DROSHA RNases to give rise to small double-stranded RNAs involved in RNA interference (RNAi). The DNA-damage response (DDR) is a signalling pathway that originates from a DNA lesion and arrests cell proliferation3. So far, DICER and DROSHA RNA products have not been reported to control DDR activation. Here we show, in human, mouse and zebrafish, that DICER and DROSHA, but not downstream elements of the RNAi pathway, are necessary to activate the DDR upon exogenous DNA damage and oncogene-induced genotoxic stress, as studied by DDR foci formation 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 RNase-A-treated cells. Through RNA deep sequencing and the study of DDR activation at a single inducible DNA double-strand break, we demonstrate that DDR foci formation requires site-specific DICER- and DROSHA-dependent small RNAs, named DDRNAs, which act in a MRE11–RAD50–NBS1-complex-dependent manner (MRE11 also known as MRE11A; NBS1 also known as NBN). DDRNAs, either chemically synthesized or in vitro generated by DICER cleavage, are sufficient to restore the 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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