Nonsense-mediated RNA decay regulation by cellular stress: implications for tumorigenesis

Abstract

Nonsense-mediated RNA decay (NMD) has long been viewed as an important constitutive mechanism to rapidly eliminate mutated mRNAs. More recently, it has been appreciated that NMD also degrades multiple nonmutated transcripts and that NMD can be regulated by wide variety of cellular stresses. Many of the stresses that inhibit NMD, including cellular hypoxia and amino acid deprivation, are experienced in cells exposed to hostile microenvironments, and several NMD-targeted transcripts promote cellular adaptation in response to these environmental stresses. Because adaptation to the microenvironment is crucial in tumorigenesis, and because NMD targets many mutated tumor suppressor gene transcripts, the regulation of NMD may have particularly important implications in cancer. This review briefly outlines the mechanisms by which transcripts are identified and targeted by NMD and reviews the evidence showing that NMD is a regulated process that can dynamically alter gene expression. Although much of the focus in NMD research has been in identifying the proteins that play a role in NMD and identifying NMD-targeted transcripts, recent data about the potential functional significance of NMD regulation, including the stabilization of alternatively spliced mRNA isoforms, the validation of mRNAs as bona fide NMD targets, and the role of NMD in tumorigenesis, are explored.

Fig 1

NMD is carried out by several multi-protein complexes. As described in the text, after introns splicing (1) nascent mRNAs contain a unique cap binding complex (CBP) as well as an exon junctional complex (EJC), and the 3’ UTR binds the poly(A) binding protein C1 (PABPC1) (2). During the pioneer round of translation (3) the EJCs are removed. In the presence of a PTC the eRF proteins recruit Upf1/Rent1, which then binds Smg1 to form the SURF complex. Upf1/Rent1 in the SURF complex bridges the EJC, and Upf1/Rent1 is phosphorylated by SMG1 (4). Subsequently SMG 5-7 are recruited, which then dephosphorylate Upf1/Rent1 (5). The mRNA is then cleaved near the PTC by endonuclease activity of SMG-6, and degraded via decapping by the decapping proteins dcp1a and dcp2, followed by exonucleases activity of xrn-1 (6). See text for details and references, including recent reviews.

Fig 2

Transcript degradation by NMD can lead to stabilization of truncated and alternatively spliced isoforms. During normal translation a full length protein is generated (left panel). A PTC normally triggers NMD, but if that transcript is stabilized via inhibition of NMD then a truncated protein may be generated, which may then serve as dominant negative or may function as a wild-type protein (middle panel). If an alternatively spliced isoform, e.g. due to a skipped exon, generates a PTC, in the absence of NMD this isoform may result in a protein with deletions or, if the alternatively spliced isoform results in a new reading frame, then a novel protein (right panel).

Fig 3

Stresses common in the tumor microenvironment can inhibit NMD via eIF2α phosphorylation. During tumor growth hypoxia and amino acid deprivation occur (top). Both of these stresses lead to eIF2a phosphorylation through the PERK and GCN2 kinase, respectively, which then inhibits NMD. The inhibition of NMD can then not only stabilize mutated tumor suppressor genes, but up-regulate a variety of cellular transcripts, including those important for the cellular response to amino acid starvation and ER stress, which then promote tumor adaptation and growth. The inhibition of NMD may also disversify the transcriptome through the stabilization of alternatively spliced isoforms (see Fig 2).