Abstract
Nonsense-mediated RNA decay (NMD) is the prototype example of a whole family of RNA decay pathways that unfold around a common central effector protein called UPF1. While NMD in yeast appears to be a linear pathway, NMD in higher eukaryotes is a multifaceted phenomenon with high variability with respect to substrate RNAs, degradation efficiency, effector proteins and decay-triggering RNA features. Despite increasing knowledge of the mechanistic details, it seems ever more difficult to define NMD and to clearly distinguish it from a growing list of other UPF1-mediated RNA decay pathways (UMDs). With a focus on mammalian NMD, we here critically examine the prevailing NMD models and the gaps and inconsistencies in these models. By exploring the minimal requirements for NMD and other UMDs, we try to elucidate whether they are separate and definable pathways, or rather variations of the same phenomenon. Finally, we suggest that the operating principle of the UPF1-mediated decay family could be considered similar to that of a computing cloud providing a flexible infrastructure with rapid elasticity and dynamic access according to specific user needs.
Highlights
Nonsense-mediated RNA decay (NMD) was originally discovered as a medically relevant cellular pathway that degrades mRNAs containing nonsense mutations in their open reading frames (ORFs), preventing the expression of truncated proteins
Such error-free NMD substrates include transcripts with upstream open reading frames, with splice events in their 3 untranslated regions (3 UTR) generated by regular alternative splicing, with exceptionally long 3 UTRs, with selenocysteine codons that are interpreted as nonsense codons in the absence of selenocysteine or undergoing programmed ribosomal frameshifting
While NMD substrates with long 3 UTRs are targeted by SMG6, endonucleolytic cleavage is considerably stimulated by the presence of exon junction complex (EJC) [89]
Summary
Nonsense-mediated RNA decay (NMD) was originally discovered as a medically relevant cellular pathway that degrades mRNAs containing nonsense mutations in their open reading frames (ORFs), preventing the expression of truncated proteins. Proteins encoded by such transcripts are often positioned at central nodes of biochemical pathways, tuning the pathways’ function, shaping the expression of whole cohorts of downstream effectors, and regulating important physiological processes such as cellular stress, development and embryogenesis [5,13,18,19,20,21,22] Such error-free NMD substrates include transcripts with upstream open reading frames (uORFs), with splice events in their 3 untranslated regions (3 UTR) generated by regular alternative splicing, with exceptionally long 3 UTRs, with selenocysteine codons that are interpreted as nonsense codons in the absence of selenocysteine or undergoing programmed ribosomal frameshifting. In higher eukaryotes, UPF2-independent, UPF3B-independent and EJC-independent NMD branches have been described (see below)
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