細胞經(jīng)常會由于各種因素產(chǎn)生帶有提前終止密碼子（Premature termination codon,， PTC）的mRNA，這些mRNA一旦翻譯成蛋白質(zhì),，就可能產(chǎn)生細胞毒性,，從而導致疾病。人類約1/3的遺傳病以及很多癌癥的突變基因都帶有提前終止密碼子,。真核細胞已經(jīng)演化出一個能夠識別并且降解這些異常轉(zhuǎn)錄本的系統(tǒng)--無義介導的mRNA降解通路（Nonsense-mediated mRNA decay,， NMD）。細胞除了基因突變產(chǎn)生帶有PTC的mRNA之外,，還有很多其它來源的mRNA也是NMD的底物（NMD靶基因）,。之前的研究發(fā)現(xiàn)，在哺乳動物中,，剪切噪聲（noisy splicing）是NMD靶基因的一個主要來源（Zhang et al, 2009, BMC Biol 7: 23）,。
中科院上海生科院/上海交大醫(yī)學院健康所孔祥銀課題組張振國等人，與英國巴斯大學Hurst教授合作,，通過對酵母中一組NMD靶基因進行系統(tǒng)的研究,，發(fā)現(xiàn)NMD靶基因的翻譯也受到很大程度的抑制。進一步研究顯示翻譯抑制是通過降低翻譯起始速率和延伸速率實現(xiàn)的,。影響因素有mRNA緊密的5’端二級結(jié)構,、較弱的啟始密碼子以及比較少的優(yōu)勢密碼子。更重要的是發(fā)現(xiàn)翻譯抑制是一個對NMD靶基因調(diào)節(jié)的新方式,，而不是NMD mRNA降解的前奏,，因為被抑制的mRNA可以在需要的時候（比如starvation）重新返回活躍的翻譯狀態(tài)。
本研究首次在基因組水平揭示NMD的靶基因不僅在mRNA水平受到降解,，而且在翻譯上受到抑制,，從而達到對這些基因產(chǎn)物的雙重抑制，并且在某些情況下通過減緩抑制的方式來調(diào)節(jié)這些基因在細胞中的蛋白豐度,。由于無義突變是人類疾病中一種常見的突變類型,，而這些突變的mRNA通常也都與NMD降解有關，本研究也為相關疾病的研究提出了新的思路,。該成果近日在線發(fā)表在Molecular Systems Biology 雜志上,。
該項工作得到了國家科技部、國家自然科學基金委和中科院項目的支持,。（生物谷Bioon.com）
生物谷推薦原文出處：
Molecular Systems Biology doi:10.1038/msb.2010.101
Nonsense-mediated decay targets have multiple sequence-related features that can inhibit translation
Zhenguo Zhang1,2,a, Li Zhou1,2, Landian Hu1, Yufei Zhu1, Heng Xu1,2, Yang Liu1,2, Xianfen Chen1,2, Xianfu Yi1,2, Xiangyin Kong1,3 & Laurence D Hurst4
The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, PR China
Graduate School of the Chinese Academy of Sciences, Beijing, PR China
State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, PR China
Department of Biology and Biochemistry, University of Bath, Bath, UK
Abstract
Nonsense-mediated mRNA decay (NMD) is a surveillance system that eliminates transcripts with premature termination codons. In this study, we show that mRNAs targeted by NMD are also suppressed at the translational level. The low translational efficiency (TE) is a consequence of multiple features acting in concert, including low translation initiation rate, mediated by 5′ secondary structure and by use of weak initiation sites, and low translation elongation speed, mediated by low codon usage bias. Despite low elongation rates, NMD transcripts show low ribosome density in the coding sequence, probably owing to low initiation rates, high abortion rates or rapid transit of the ribosome following initiation failure. The low TE is observed in the absence of NMD and is not explained by low transcript abundance. Translational inefficiency is flexible, such that NMD targets have increased TE upon starvation. We propose that the low TE predisposes to NMD and/or that it is part of a mechanism for regulation of NMD transcripts.
