MicroRNA-mediated repression of nonsense mRNAs.
MicroRNA-mediated repression of nonsense mRNAs.
复制标题
MicroRNA 介导的无义 mRNA 抑制。
作者：
Zhao Y;Lin J;Xu B;Hu S;Zhang X;Wu L
许多研究已经确定了microRNAs(MiRNAs)在基因表达调控中的重要作用。在这里，我们报告miRNAs还可以作为一个监测系统来抑制可能产生有害截断蛋白的无意义mRNAs的表达。当翻译的核糖体识别出过早终止密码子时，mRNA编码区的下游部分被重新定义为3‘非翻译区的一部分，结果是，嵌入该区域的miRNA反应元件可以被miRNAs检测到，从而触发加速的mRNA去烯化和翻译抑制。我们证明了自然发生的致癌APC(结肠腺瘤性息肉病)无义突变体逃脱了无义介导的mRNA衰退(NMD)，被miRNA介导的监视抑制。此外，我们还表明miRNA介导的监视和外显子-外显子连接复合体介导的NMD并不是相互排斥的，而是相加地作用于增强抑制活性。因此，我们发现了miRNAs在抑制无意义突变mRNAs中的新作用。DOI：http://dx.doi.org/10.7554/eLife.03032.001要从基因中产生蛋白质，基因的序列必须被转录以产生信使核糖核酸分子。然后，以三个字母为一组(称为密码子)一组地读取该信使核糖核酸的序列，每个密码子指示将一种特定的氨基酸添加到蛋白质中。然而，有些密码子并不编码氨基酸，相反，这些“终止密码子”标志着蛋白质的结束。如果DNA字母被添加、丢失或改变，这种突变有时会在mRNA序列中过早地产生终止密码子。这被称为无义突变，会产生截短的蛋白质，要么不能正常工作，要么根本不能工作，这可能会损害生物体。例如，人类肿瘤抑制基因APC发生无义突变的人比没有这种突变的人更有可能患结肠癌。APC通常会阻止细胞不受控制的生长和分裂。人体细胞使用几种不同的监测机制来检测无义突变。最广为人知的机制涉及一个称为外显子-外显子连接复合体(EJC)的大蛋白质群，它与mRNA中的位点结合。在蛋白质的生产过程中，细胞翻译机制移除了所有与正常mRNA结合的EjCs。如果翻译机器过早地到达终止密码子，那么位于其下游的EjC就不会被移除，信使核糖核酸分子就会被破坏。然而，这种机制并不适用于所有基因--包括APC。非常短的RNA片段称为microRNAs，通过导致mRNAs降解和抑制其翻译来调节蛋白质的产生，赵等人说。现在发现，microRNAs还可以防御APC基因的无义突变。过早的终止密码子会使microRNA分子与之结合的信使核糖核酸分子上更多的位点暴露出来，从而触发信使核糖核酸的分解并抑制其翻译。MicroRNA监测系统独立于涉及EJC的系统工作。然而，这两种机制可以并行工作，这为防止无义突变提供了额外的保护。赵等人。还发现，microRNAs可以防止在人类细胞中发现的其他几种类型的基因发生无义突变。因此，监测microRNA很可能是细胞用来限制潜在有害截断蛋白产生的一种常见方法。DOI：http://dx.doi.org/10.7554/eLife.03032.002
Numerous studies have established important roles for microRNAs (miRNAs) in regulating gene expression. Here, we report that miRNAs also serve as a surveillance system to repress the expression of nonsense mRNAs that may produce harmful truncated proteins. Upon recognition of the premature termination codon by the translating ribosome, the downstream portion of the coding region of an mRNA is redefined as part of the 3′ untranslated region; as a result, the miRNA-responsive elements embedded in this region can be detected by miRNAs, triggering accelerated mRNA deadenylation and translational inhibition. We demonstrate that naturally occurring cancer-causing APC (adenomatous polyposis coli) nonsense mutants which escape nonsense-mediated mRNA decay (NMD) are repressed by miRNA-mediated surveillance. In addition, we show that miRNA-mediated surveillance and exon–exon junction complex-mediated NMD are not mutually exclusive and act additively to enhance the repressive activity. Therefore, we have uncovered a new role for miRNAs in repressing nonsense mutant mRNAs. DOI: http://dx.doi.org/10.7554/eLife.03032.001 To produce a protein from a gene, the sequence of the gene must be transcribed to produce a molecule of messenger RNA (mRNA). The sequence of the mRNA is then read in groups of three letters at a time (called codons), and each codon instructs for a particular amino acid to be added into the protein. Some codons, however, do not code for an amino acid and instead these ‘stop codons’ mark the end of a protein. If a DNA letter is added, lost, or changed, this mutation can sometimes produce a stop codon too early in the mRNA sequence. This is called a nonsense mutation, and produces truncated proteins that either work incorrectly or do not work at all, which can harm the organism. For example, people with a nonsense mutation in the human tumor suppressor gene called APC—which normally stops uncontrolled cell growth and division—are more likely to develop colon cancer than people without this mutation. Cells in the body employ several different surveillance mechanisms to detect nonsense mutations. The best-known mechanism involves a large protein group called the exon–exon junction complex (EJC), which binds to sites within the mRNA. The cellular translation machinery removes all the EJCs bound to a normal mRNA during the production of proteins. If the translation machinery reaches a stop codon too early, so that EJCs located downstream of it are not removed, the mRNA molecule is destroyed. However, this mechanism does not work for all genes—including APC. Very short sections of RNA called microRNAs regulate protein production by causing mRNAs to degrade and by inhibiting their translation, and Zhao et al. have now found that microRNAs also act as a defense against nonsense mutations in the APC gene. A premature stop codon exposes sites further along the mRNA molecule that microRNA molecules bind to, which triggers the breaking down of the mRNA and inhibits its translation. The microRNA surveillance system works independently of the system involving the EJC. However, both mechanisms can work in parallel alongside each other, which provides extra protection against nonsense mutations. Zhao et al. also found that microRNAs can protect against nonsense mutations in several other types of gene found in human cells. Therefore, microRNA surveillance is likely to be a common method employed by cells to restrict the production of potentially harmful truncated proteins. DOI: http://dx.doi.org/10.7554/eLife.03032.002