Neu-Yilik Gabriele, Kulozik Andreas E
Department for Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg and Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany.
Adv Genet. 2008;62:185-243. doi: 10.1016/S0065-2660(08)00604-4.
Gene expression is a highly specific and regulated multilayer process with a plethora of interconnections as well as safeguard and feedback mechanisms. Messenger RNA, long neglected as a mere subcarrier of genetic information, is more recently recognized as a linchpin of regulation and control of gene expression. Moreover, the awareness of not only proteins but also mRNA as a modulator of genetic disorders has vastly increased in recent years. Nonsense-mediated mRNA decay (NMD) is a posttranscriptional surveillance mechanism that uses an intricate network of nuclear and cytoplasmic processes to eliminate mRNAs, containing premature termination codons. It thus helps limit the synthesis of potentially harmful truncated proteins. However, recent results suggest functions of NMD that go far beyond this role and affect the expression of wild-type genes and the modulation of whole pathways. In both respects--the elimination of faulty transcripts and the regulation of error-free mRNAs--NMD has many medical implications. Therefore, it has earned increasing interest from researchers of all fields of the life sciences. In the following text, we (1) present current knowledge about the NMD mechanism and its targets, (2) define its relevance in the regulation of important biochemical pathways, (3) explore its medical significance and the prospects of therapeutic interventions, and (4) discuss additional functions of NMD effectors, some of which may be networked to NMD. The main focus of this chapter lies on mammalian NMD and resorts to the features and factors of NMD in other organisms if these help to complete or illuminate the picture.
基因表达是一个高度特异且受调控的多层级过程，有着大量的相互联系以及保障和反馈机制。信使核糖核酸（mRNA）长期以来被视为仅仅是遗传信息的载体而受到忽视，最近却被认为是基因表达调控的关键所在。此外，近年来人们不仅认识到蛋白质，还认识到mRNA作为遗传疾病调节因子的重要性大幅增加。无义介导的mRNA降解（NMD）是一种转录后监测机制，它利用细胞核和细胞质中复杂的过程网络来消除含有提前终止密码子的mRNA。因此，它有助于限制潜在有害的截短蛋白的合成。然而，最近的研究结果表明，NMD的功能远不止于此，它还会影响野生型基因的表达以及整个信号通路的调节。在消除错误转录本和调节无错误mRNA这两个方面，NMD都具有许多医学意义。因此，它引起了生命科学各个领域研究人员越来越多的关注。在下文，我们（1）介绍关于NMD机制及其靶点的现有知识，（2）明确其在重要生化信号通路调节中的相关性，（3）探讨其医学意义以及治疗干预的前景，（4）讨论NMD效应因子的其他功能，其中一些可能与NMD相互关联。本章的主要重点是哺乳动物的NMD，如果其他生物体中NMD的特征和因素有助于完善或阐明相关情况，也会加以引用。
