Abstract
Nonsense-mediated mRNA decay (NMD), which is arguably the best-characterized translation-dependent regulatory pathway in mammals, selectively degrades mRNAs as a means of post-transcriptional gene control. Control can be for the purpose of ensuring the quality of gene expression. Alternatively, control can facilitate the adaptation of cells to changes in their environment. The key to NMD, no matter what its purpose, is the ATP-dependent RNA helicase upstream frameshift 1 (UPF1), without which NMD fails to occur. However, UPF1 does much more than regulate NMD. As examples, UPF1 is engaged in functionally diverse mRNA decay pathways mediated by a variety of RNA-binding proteins that include staufen, stem–loop-binding protein, glucocorticoid receptor, and regnase 1. Moreover, UPF1 promotes tudor-staphylococcal/micrococcal-like nuclease-mediated microRNA decay. In this review, we first focus on how the NMD machinery recognizes an NMD target and triggers mRNA degradation. Next, we compare and contrast the mechanisms by which UPF1 functions in the decay of other mRNAs and also in microRNA decay. UPF1, as a protein polymath, engenders cells with the ability to shape their transcriptome in response to diverse biological and physiological needs.
Highlights
The ATP-dependent RNA helicase upstream frameshift 1 (UPF1) is required for the nonsense-mediated mRNA decay (NMD) of all eukaryotic NMD targets studied to date (Brogna et al 2016; Hug et al 2016; Karousis et al 2016; Saveanu and Jacquier 2016; Celik et al 2017; Karousis and Mühlemann 2018; Raimondeau et al 2018)
We subsequently introduce possible variations of this model to accommodate that there are branches of NMD that differ in their requirement for particular NMD factors
After that, phosphorylated UPF1 recruits protein-rich nuclear receptor coactivator 2 (PNRC2) that, as it does during NMD, elicits decapping followed by 5′-to-3′ exoribonucleolytic cleavage of STAUFEN-MEDIATED mRNA DECAY (SMD)-targeted mRNAs (Cho et al 2009, 2012)
Summary
The ATP-dependent RNA helicase upstream frameshift 1 (UPF1) is required for the nonsense-mediated mRNA decay (NMD) of all eukaryotic NMD targets studied to date (Brogna et al 2016; Hug et al 2016; Karousis et al 2016; Saveanu and Jacquier 2016; Celik et al 2017; Karousis and Mühlemann 2018; Raimondeau et al 2018). Once UPF1 is phosphorylated, the NMD substrate is further remodeled so that additional translation initiation events are precluded and mRNA degradative activities are recruited, both of which are required for mRNA decay (see below).
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