NMD: multitasking between mRNA surveillance and modulation of gene expression.

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.