生物谷報(bào)道：近日公布在Cell雜志上的一篇研究報(bào)道稱,，來自美國紐約約斯隆/凱德琳癌癥研究中心（Memorial Sloan-Kettering Cancer Center）發(fā)育生物學(xué)系的研究人員發(fā)現(xiàn)了一種不同于正常miRNAs合成途徑的新途徑,，這為進(jìn)一步解釋生物RNA沉默機(jī)制提供了重要資料以及新的思路。 RNA沉默是存在于生物中的一種古老現(xiàn)象, 是生物抵抗異常DNA(病毒,、轉(zhuǎn)座因子和某些高重復(fù)的基因組序列)的保護(hù)機(jī)制, 同時(shí)在生物發(fā)育過程中扮演著基因表達(dá)調(diào)控的角色,，它可以通過降解RNA、抑制翻譯或修飾染色體等方式發(fā)揮作用,。
RNA沉默存在兩種既有聯(lián)系又有區(qū)別的途徑: siRNA(small interference RNA)途徑和miRNA(microRNA)途徑,。siRNA途徑是由dsRNA(double-stranded RNA)引發(fā)的, dsRNA被一種RNaseⅢ家族的內(nèi)切核酸酶(RNA- induced silencing complex, Dicer)切割成21~26 nt長的siRNA, 通過siRNA指導(dǎo)形成RISC蛋白復(fù)合物(RNA-induced silencing complex)降解與siRNA序列互補(bǔ)的mRNA而引發(fā)RNA沉默。而miRNA途徑中miRNA是含量豐富的不編碼小RNA(21~24個(gè)核苷酸), 由Dicer酶切割內(nèi)源性表達(dá)的短發(fā)夾結(jié)構(gòu)RNA(hairpin RNA, hpRNA)形成,。miRNA同樣可以與蛋白因子形成RISC蛋白復(fù)合物, 可以結(jié)合并切割特異的mRNA而引發(fā)RNA沉默,。盡管引發(fā)沉默的來源不同, 但siRNA 和miRNA 都參與構(gòu)成結(jié)構(gòu)相似的RISC, 在作用方式上二者有很大的相似性。
在這篇文章中,，研究人員描繪了果蠅的一種由短小的內(nèi)含子發(fā)夾結(jié)構(gòu)形成的miRNAs,，并將其命名為“mirtrons”。這些miRNAs的關(guān)鍵生物生成過程好像避開了Drosha的剪切,，而這對(duì)于miRNA生物合成是必需的,。
那么mirtrons是如何形成的呢？研究人員發(fā)現(xiàn)mirtrons的剪切機(jī)制是通過lariat-debranching酶產(chǎn)生miRNA類前體發(fā)夾,。并且在Exportin-5發(fā)夾端口處融入到了正常的miRNA途徑過程中,，這兩種發(fā)夾可以被之后的途徑中的Dicer-1/loqs處理。這樣得到的小RNAs可以很好的匹配靶標(biāo),，而且研究人員證明這些miRNAs至少能部分的行使功能——通過RNA誘導(dǎo)的沉默復(fù)合效應(yīng)子Ago1,。
這些研究成果意義重大,，揭示了mirtrons可能是另外一種miRNA型調(diào)控性RNAs，這為進(jìn)一步解釋生物RNA沉默機(jī)制提供了重要資料以及新的思路,。
原始出處:
Cell, Vol 130, 89-100, 13 July 2007
The Mirtron Pathway Generates microRNA-Class Regulatory RNAs in Drosophila
Katsutomo Okamura,1 Joshua W. Hagen,1 Hong Duan,1 David M. Tyler,1 and Eric C. Lai1,
1 Memorial Sloan-Kettering Cancer Center, Department of Developmental Biology, 1275 York Ave, Box 252, New York, NY 10021, USA
Corresponding author
Eric C. Lai
[email protected]
Summary
The canonical microRNA (miRNA) pathway converts primary hairpin precursor transcripts into ∼22 nucleotide regulatory RNAs via consecutive cleavages by two RNase III enzymes, Drosha and Dicer. In this study, we characterize Drosophila small RNAs that derive from short intronic hairpins termed “mirtrons.” Their nuclear biogenesis appears to bypass Drosha cleavage, which is essential for miRNA biogenesis. Instead, mirtron hairpins are defined by the action of the splicing machinery and lariat-debranching enzyme, which yield pre-miRNA-like hairpins. The mirtron pathway merges with the canonical miRNA pathway during hairpin export by Exportin-5, and both types of hairpins are subsequently processed by Dicer-1/loqs. This generates small RNAs that can repress perfectly matched and seed-matched targets, and we provide evidence that they function, at least in part, via the RNA-induced silencing complex effector Ago1. These findings reveal that mirtrons are an alternate source of miRNA-type regulatory RNAs.
