真核生物无义介导的mRNA降解与肿瘤关系的研究进展

Progress in the Research of NMD in Tumors

研究发现任何错误剪接、移码、插入等基因突变都可能引入含有提前终止密码子(premature termination codon,PTC)的转录产物,将导致翻译提前终止而产生无生物活性甚至毒害性截短蛋白(truncated proteins)。而无义介导的mRNA的降解(nonsensemediated m RNA decay,NMD)作用机制在基因转录及转录后加工过程中选择性地迅速降解含有提前终止密码子的mRNA,避免产生对细胞正常生理功能有害的截短蛋白,真核生物NMD是转录后m RNA监控的重要环节。肿瘤的发生发展与相应基因的表达有关,NMD可以降解含有PTC的mRNA,学者们认为抑制NMD后肿瘤中某些基因的表达上调,而上调的基因或许在肿瘤的发生发展中其抑癌基因的作用,故学者们抑制肿瘤中NMD后进行测序筛选发生无义突变的抑癌基因。

Nonsense-mediated mRNA decay （NMD）, a highly conserved mechanism which prevents the expression ofmRNAs containing premature termination codon （PTC） and maintains normal transcfiptome homeostasis. The core NMD factors were firstly identified in genetic screens in Saccharomyces cerevisae and in the nematode Caenorhabditis elegans, and subsequently by homology searches in other mammalian. Nonsense and ffameshift mutations that generate PTCs cause approximately one-third of all known human genetic diseases and thus NMD has a potentially important role in human disease. A strategy referred to as gene identification by NMD inhibition （GINI） has proved successful in identifying sporadic nonsense mutations involved in many different cancer types.