The long and short of EJC-independent nonsense-mediated RNA decay

Abstract

Nonsense-mediated RNA decay (NMD) plays a dual role as an RNA surveillance mechanism against aberrant transcripts containing premature termination codons and as a gene regulatory mechanism for normal physiological transcripts. This dual function is possible because NMD recognizes its substrates based on the functional definition of a premature translation termination event. An efficient mode of NMD target recognition involves the presence of exon-junction complexes (EJCs) downstream of the terminating ribosome. A less efficient, but highly conserved, mode of NMD is triggered by long 3' untranslated regions (UTRs) that lack EJCs (termed EJC-independent NMD). While EJC-independent NMD plays an important regulatory role across organisms, our understanding of its mechanism, especially in mammalian cells, is incomplete. This review focuses on EJC-independent NMD and discusses the current state of knowledge and factors that contribute to the variability in the efficiency of this mechanism.

Keywords: RNA decay; alternative splicing; exon-junction complexes; nonsense-mediated decay; translation.

Figure 1. EJC-dependent versus EJC-independent NMD Mechanisms.

A) EJC-dependent NMD requires an exon junction complex (EJC) downstream of the terminating ribosome. When this condition is met, UPF1–3 and eRF1 binds the EJC. B) EJC-independent NMD relies on recognition of an abnormal termination context in the absence of downstream EJCs. The proximity of PABPC1 to the termination codon may inhibit EJC-independent NMD. Nucleases degrade the released transcript after ribosomal dissociation. Both pathways require UPF1 surveillance and hyperphosphorylation of UPF1 by SMG1, which causes the ribosome to release from the transcript and subsequent transcript degradation by recruited nucleases.

Figure 2. Factors that allow evasion of EJC-independent NMD.

Trans elements that inhibit NMD include endogenous and exogenous RNA binding proteins such as PTBP1 and REV, which encumber UPF1 surveillance. Cis elements inhibit NMD by sequestering NMD-inhibiting RBPs with their structure and sequence, by promoting readthrough and frameshifts and reinitiation, or by the lack of structural stability.