近日,，中科院上海生命科學(xué)研究院/上海交通大學(xué)醫(yī)學(xué)院健康科學(xué)研究所分子遺傳（孔祥銀）課題組博士生張振國等人發(fā)現(xiàn)RNA剪接噪音是導(dǎo)致細(xì)胞內(nèi)豐富提前終止密碼子形成的重要原因,。該成果在線發(fā)表在BMC Biology雜志上,。
高等生物細(xì)胞內(nèi)存在大量含有提前終止密碼子的mRNA,。含有提前終止密碼子的mRNA可以被無義介導(dǎo)的mRNA降解機制降解,。問題是細(xì)胞為什么要產(chǎn)生大量注定要被無義介導(dǎo)的mRNA降解機制降解的mRNA? 一個模型是基因轉(zhuǎn)錄、RNA剪接具有不可避免的高噪音(Splicing noise),，雜散轉(zhuǎn)錄產(chǎn)物是常見的,。這些雜散轉(zhuǎn)錄產(chǎn)物很可能是有害的,。為防止高成本的翻譯,，他們必須被清除,。另一個模型是在某些情況下， 如環(huán)境脅迫,，無義介導(dǎo)的mRNA降解是可以被調(diào)節(jié)的;通過抑制無義介導(dǎo)的mRNA降解,，可以上調(diào)含有提前終止密碼子mRNA的豐度。
孔祥銀課題組與英國巴斯大學(xué)Hurst教授合作,，通過對人和小鼠轉(zhuǎn)錄組的系統(tǒng)研究,，發(fā)現(xiàn)細(xì)胞內(nèi)豐富提前終止密碼子主要是由于RNA剪切噪音產(chǎn)生，支持Splicing noise模型,。但是,，古老外顯子上的提前終止密碼子，通過與無義介導(dǎo)的mRNA降解配合, 調(diào)節(jié)基因翻譯,，是一個更合理的解釋,。
該項工作得到了國家科技部、國家自然科學(xué)基金委和中科院項目的支持,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
