隨著人們對生物領(lǐng)域研究的深入，非編碼RNA(non-coding RNAs, ncRNAs)在一系列生物學(xué)事件中的作用被越來越多的發(fā)現(xiàn)和認識,。比如，一些ncRNA可以在DICER和DROSHA的作用下切割成短的雙鏈小RNA,，這些小RNA靶向沉默細胞內(nèi)的mRNA,，這也就是我們常說的RNA干擾。
DNA損傷應(yīng)答（DNA-damage response,，DDR）是指有機體DNA受到損傷時細胞增殖停滯的一種反應(yīng),，在DNA損傷發(fā)生后，DDR通過募集大量蛋白形成蛋白簇集點,，來感應(yīng)和傳導(dǎo)損傷信號,。迄今為止，還沒有研究把DICER和DROSHA的加工產(chǎn)物與細胞的DDR途徑聯(lián)系起來,。
本文中，研究者發(fā)現(xiàn)在人類,、小鼠和斑馬魚中,，DICER和DROSHA是激活DDR途徑所必須的，而RNAi途徑的下游分子對DDR的激活沒有影響,。通過對DDR蛋白簇集點和對細胞周期檢驗點的分析,，研究人員指出DDR蛋白簇集點對RNA酶A敏感，而DICER和DROSHA的加工產(chǎn)物在修復(fù)RNA酶A處理過的細胞DDR蛋白簇集點中是必須的,。通過對RNA深度測序和對雙鏈DNA斷裂的細胞中DDR活性的檢測,，研究人員證明了，DDR蛋白簇集點的形成需要一類小RNA的參與,，這類名為DDRNA的小RNA正是DICER與DROSHA的加工產(chǎn)物,。該研究揭示了非編碼RNA一項意想不到的新功能，同時使我們對DDR途徑有了新的認識,。（生物谷 Bioon.com ）
doi:10.1038/nature11061
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PMID:
Site-specific DICER and DROSHA RNA products control the DNA-damage response
Sofia Francia, Flavia Michelini, Alka Saxena, Dave Tang, Michiel de Hoon, Viviana Anelli, Marina Mione, Piero Carninci & Fabrizio d’Adda di Fagagna
Non-coding RNAs (ncRNAs) are involved in an increasingly recognized number of cellular events1. Some ncRNAs are processed by DICER and DROSHA RNases to give rise to small double-stranded RNAs involved in RNA interference (RNAi)2. 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.
