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. 2013 Jun-Jul;1829(6-7):624-33.
doi: 10.1016/j.bbagrm.2013.03.002. Epub 2013 Mar 13.

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

Rachid Karam  1 , Jordan Wengrod, Lawrence B Gardner, Miles F Wilkinson
Affiliations

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

Rachid Karam et al. Biochim Biophys Acta. 2013 Jun-Jul.

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. This article is part of a Special Issue entitled: RNA Decay mechanisms.

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Figures

Fig. 1
Fig. 1. MiRNA-mediated regulation of NMD
(A) The miRNA miR-128 directly represses the level of the NMD factor UPF1 and the EJC core component MLN51, which leads to low NMD activity. (B) AGO2, which is recruited to the 3’ UTR of mRNAs by miRNAs, displaces the cap-binding complex (CBP) from the 5’ cap, thereby inhibiting the translation of exon-junction complex (EJC)-bound mRNAs, which, in turn, inhibits the decay of these mRNAs by NMD.
Fig. 2
Fig. 2. Autoregulation of NMD
(A) The mRNAs encoding seven NMD factors— UPF1, UPF2, UPF3B, SMG1, SMG5, SMG6 and SMG7—are degraded by NMD. This provides a buffering mechanism to preserve the integrity of NMD. In response to a stress that inhibits NMD, these mRNAs are stabilized, allowing higher levels of NMD factors to be translated for compensation. (B) Evidence suggests that the NMD factor UPF3A is highly unstable unless it binds to the NMD factor UPF2. Because UPF3A is outcompeted by its paralog, UPF3B, for binding to the NMD factor UPF2, UPF3A levels are normally low. However when UPF3B is depleted or lost, this allows much more UPF3A to bind to UPF2, leading to a dramatic increase in UPF3A levels, which permits a partial rescue of NMD. This cross-regulatory mechanism has the potential to influence the intellectually disability and psychiatric symptoms of patients with mutations in UPF3B.
Fig. 3
Fig. 3. Mechanisms that inhibit NMD in response to stress
Many kinds of stress activate protein kinases that phosphorylate eukaryotic initiation factor 2α (eIF2α), an event that, in turn, inhibits NMD. In part, NMD may be inhibited because eIF2α phosphorylation suppresses protein translation, a process absolutely required for NMD. However, suppression of translation is unlikely to be the only mechanism by which eIF2α phosphorylation represses NMD, as eIF2α phosphorylation does not completely block translation and stress does not prevent NMD mRNA targets from being translated.
Fig. 4
Fig. 4. Inhibited NMD impacts tumorigenesis
A variety of cellular stresses typically present in tumors inhibit eIF2α phosphorylation, which, in turn, represses NMD. Suppressed NMD can, in theory, either promote or inhibit tumors (see text). Shown is a scenario that promotes tumor formation: stabilization of aberrant NMD target mRNAs encoding mutant dominant-negative tumor suppressor proteins (e.g., DN-BRCA1) and normal NMD target mRNAs that encode pro-tumor proteins and proteins that promote cellular adaptation to stress (e.g., ATF4).
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