细胞经常会由于各种因素产生带有提前终止密码子（Premature termination codon， PTC）的mRNA，这些mRNA一旦翻译成蛋白质，就可能产生细胞毒性，从而导致疾病。人类约1/3的遗传病以及很多癌症的突变基因都带有提前终止密码子。真核细胞已经演化出一个能够识别并且降解这些异常转录本的系统--无义介导的mRNA降解通路（Nonsense-mediated mRNA decay， NMD）。细胞除了基因突变产生带有PTC的mRNA之外，还有很多其它来源的mRNA也是NMD的底物（NMD靶基因）。之前的研究发现，在哺乳动物中，剪切噪声（noisy splicing）是NMD靶基因的一个主要来源（Zhang et al, 2009, BMC Biol 7: 23）。
中科院上海生科院/上海交大医学院健康所孔祥银课题组张振国等人，与英国巴斯大学Hurst教授合作，通过对酵母中一组NMD靶基因进行系统的研究，发现NMD靶基因的翻译也受到很大程度的抑制。进一步研究显示翻译抑制是通过降低翻译起始速率和延伸速率实现的。影响因素有mRNA紧密的5’端二级结构、较弱的启始密码子以及比较少的优势密码子。更重要的是发现翻译抑制是一个对NMD靶基因调节的新方式，而不是NMD mRNA降解的前奏，因为被抑制的mRNA可以在需要的时候（比如starvation）重新返回活跃的翻译状态。
本研究首次在基因组水平揭示NMD的靶基因不仅在mRNA水平受到降解，而且在翻译上受到抑制，从而达到对这些基因产物的双重抑制，并且在某些情况下通过减缓抑制的方式来调节这些基因在细胞中的蛋白丰度。由于无义突变是人类疾病中一种常见的突变类型，而这些突变的mRNA通常也都与NMD降解有关，本研究也为相关疾病的研究提出了新的思路。该成果近日在线发表在Molecular Systems Biology 杂志上。
该项工作得到了国家科技部、国家自然科学基金委和中科院项目的支持。（生物谷Bioon.com）
生物谷推荐原文出处：
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.
