Regulation of nonsense-mediated mRNA decay: Implications for physiology and disease

Abstract

Nonsense-mediated mRNA decay (NMD) is an mRNA quality control mechanism that destabilizes aberrant mRNAs harboring premature termination (nonsense) codons (PTCs). Recent studies have shown that NMD also targets mRNAs transcribed from a large subset of wild-type genes. This raises the possibility that NMD itself is under regulatory control. Indeed, several recent studies have shown that NMD activity is modulated in specific cell types and that key components of the NMD pathway are regulated by several pathways, including microRNA circuits and NMD itself. Cellular stress also modulates the magnitude of NMD by mechanisms that are beginning to be understood. Here, we review the evidence that NMD is regulated and discuss the physiological role for this regulation. We propose that the efficiency of NMD is altered in some cellular contexts to regulate normal biological events. In disease states—such as in cancer—NMD is disturbed by intrinsic and extrinsic factors, resulting in altered levels of crucial NMD-targeted mRNAs that lead to downstream pathological consequences.

Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay

“…In addition, a continuous cycle of UPF1 phosphorylation by SMG1 kinase and UPF1 dephosphorylation by phosphatase 2A is essential for efficient NMD (Karam et al 2013;Fatscher et al 2015;Lykke-Andersen and Jensen 2015). In particular, a phosphorylated form of UPF1 more strongly associates with adaptors or effectors such as PNRC2 and SMG5-7 and ′ -RLuc mRNAs in the cells untreated with Dex were arbitrarily set to 100%.…”

“…It is known that GMD factors PNRC2 and UPF1 are commonly involved in multiple types of mRNA decay pathway (Cho et al , 2013Lai et al 2012;Choe et al 2014a): nonsense-mediated mRNA decay (NMD), which specifically recognizes and removes aberrant mRNAs containing a premature termination codon (PTC); staufen-mediated mRNA decay (SMD), which triggers rapid degradation of mRNAs containing the staufenbinding site in the 3 ′ untranslated region (UTR); and replication-dependent histone mRNA decay (HMD), which is an mRNA degradation pathway activated during the cell cycle (Marzluff et al 2008;Karam et al 2013;Fatscher et al 2015; Lykke-Andersen and Jensen 2015; Karousis et al 2016). It should be noted that NMD, SMD, and HMD are dependent on a translation event.…”

Caspases shutdown nonsense-mediated mRNA decay during apoptosis

“…One of these, nonsense-mediated mRNA decay (NMD), leads to the rapid decay of mRNAs harboring a premature termination codon (PTC) to prevent the synthesis of non-functional and/or potentially detrimental truncated proteins. [8][9][10] In addition to its role in quality control, NMD also regulates gene expression of so-called natural substrates of NMD. [11][12][13][14][15] Proteins that have a central role in NMD, such as UPF1, UPF2, UPF3/UPF3a and UPF3X/UPF3b are highly conserved from yeast to human.…”

eIF4AIII enhances translation of nuclear cap-binding complex–bound mRNAs by promoting disruption of secondary structures in 5′UTR

“…It has long been thought that nonsense-mediated mRNA decay (NMD), which drives selective destruction of aberrant or physiological mRNAs containing a premature termination codon (9)(10)(11), occurs during the first round of translation driven by the CBC (1). The above view, however, was recently challenged by two reports showing that NMD occurs in the cytoplasm, regardless of whether the CBC or eIF4E drives the first round of translation (12,13).…”