近日，中科院上海生命科学研究院/上海交通大学医学院健康科学研究所分子遗传（孔祥银）课题组博士生张振国等人发现RNA剪接噪音是导致细胞内丰富提前终止密码子形成的重要原因。该成果在线发表在BMC Biology杂志上。

　　高等生物细胞内存在大量含有提前终止密码子的mRNA。含有提前终止密码子的mRNA可以被无义介导的mRNA降解机制降解。问题是细胞为什么要产生大量注定要被无义介导的mRNA降解机制降解的mRNA?  一个模型是基因转录、RNA剪接具有不可避免的高噪音(Splicing  noise)，杂散转录产物是常见的。这些杂散转录产物很可能是有害的。为防止高成本的翻译，他们必须被清除。另一个模型是在某些情况下，  如环境胁迫，无义介导的mRNA降解是可以被调节的;通过抑制无义介导的mRNA降解，可以上调含有提前终止密码子mRNA的丰度。

　　孔祥银课题组与英国巴斯大学Hurst教授合作，通过对人和小鼠转录组的系统研究，发现细胞内丰富提前终止密码子主要是由于RNA剪切噪音产生，支持Splicing  noise模型。但是，古老外显子上的提前终止密码子，通过与无义介导的mRNA降解配合,  调节基因翻译，是一个更合理的解释。

　　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。

　　推荐原始出处：

　　BMC Biol. 2009 May 14;7(1):23.

　　Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay.

　　Zhang Z, Xin D, Wang P, Zhou L, Hu L, Kong X, Hurst LD.

　　ABSTRACT: BACKGROUND: Nonsense-mediated decay is a mechanism that degrades mRNAs with a premature termination codon. That some exons have premature termination codons at fixation is paradoxical: why make a transcript if it is only to be destroyed? One model supposes that splicing is inherently noisy and spurious transcripts are common. The evolution of a premature termination codon in a regularly made unwanted transcript can be a means to prevent costly translation. Alternatively, nonsense-mediated decay can be regulated under certain conditions so the presence of a premature termination codon can be a means to up-regulate transcripts needed when nonsense-mediated decay is suppressed. RESULTS: To resolve this issue we examined the properties of putative nonsense-mediated decay targets in humans and mice. We started with a well-annotated set of protein coding genes and found that 2 to 4% of genes are probably subject to nonsense-mediated decay, and that the premature termination codon reflects neither rare mutations nor sequencing artefacts. Several lines of evidence suggested that the noisy splice model has considerable relevance: 1) exons that are uniquely found in nonsense-mediated decay transcripts (nonsense-mediated decay-specific exons) tend to be newly created; 2) have low-inclusion level; 3) tend not to be a multiple of three long; 4) belong to genes with multiple splice isoforms more often than expected; and 5) these genes are not obviously enriched for any functional class nor conserved as nonsense-mediated decay candidates in other species. However, nonsense-mediated decay-specific exons for which distant orthologous exons can be found tend to have been under purifying selection, consistent with the regulation model. CONCLUSION: We conclude that for recently evolved exons the noisy splicing model is the better explanation of their properties, while for ancient exons the nonsense-mediated decay regulated gene expression is a viable explanation.