The intimate relationships of mRNA decay and translation

Abstract

The decay rate of an mRNA and the efficiency with which it is translated are key determinants of eukaryotic gene expression. Although it was once thought that mRNA stability and translational efficiency were directly linked, the interrelationships between the two processes are considerably more complex. The decay of individual mRNAs can be triggered or antagonized by translational impairment, and alterations in the half-life of certain mRNAs can even alter translational fidelity. In this review we consider whether mRNA translation and turnover are distinct or overlapping phases of an mRNA life cycle, and then address some of the many ways in which the two processes influence each other in eukaryotic cells.

Keywords: mRNA degradation; quality control; translational repression.

Figure 1. Decay pathways for normal mRNAs and mRNAs undergoing translational control

mRNAs enter the cytoplasm where they get translated after associating with ribosomes and are subjected to multiple modes of post-transcriptional regulation, including: (A) mRNA degradation initiated by poly(A) shortening (catalyzed by the Ccr4–Not and poly(A)-specific deadenylases). Deadenylation is followed by 5´ −3´ decapping-dependent, Xrn1-mediated exonucleolytic decay, or, exosome-mediated 3´ -5´ exonucleolytic decay. Association of the Lsm1–7 complex with the 3’ end of the mRNA stimulates Dcp1-Dcp2-mediated decapping. (B) Untranslated transcripts are assembled into RNA-protein cytoplasmic granules called P-bodies together with the mRNA-decapping enzyme complex (Dcp1-Dcp2), Xrn1, Pat1, Dhh1, and Lsm1–Lsm7. (C) PUF proteins mediate translation repression and mRNA decay by directly binding to PUF binding elements in the mRNA or other protein partners (such as Nanos, Brat, or CPEB; not shown) in a transcript-specific manner. Recruitment of the Ccr4-Not deadenylase complex can trigger deadenylation-dependent mRNA decay. (D) Binding of the RISC complex triggers inhibition of translation initiation by interfering with cap recognition, 40S recruitment, or with 60S subunit joining. Interaction of RISC with the Ccr4-Not deadenylase complex also triggers deadenylation-dependent mRNA degradation. (E) Decapping activators stimulate mRNA decapping and inhibit translation during 48S formation (Pat1, Dhh1, Scd6) or during 80S formation (Stm1).

Figure 2. Abnormal translational events leading to accelerated mRNA decay

The three major mRNA surveillance mechanisms are represented on the same mRNA. Initiation of NMD, NGD, and NSD involve recognition of abnormal translation events – a premature termination event (NMD), an elongation stall (NGD), and poly(A) translation (NSD), respectively. Recognition of the abnormal ribosomal complexes is followed by mRNA decay and proteasome-mediated degradation of the nascent peptide in all three pathways. In NMD, following recognition of a premature termination event by the Upf factors, the mRNA is subjected to accelerated decapping involving the Dcp1-Dcp2 complex. Recognition of a stalled ribosomal complex in NGD is followed by endonucleolytic cleavage of the mRNA upstream of the stalled ribosome in a Dom34-Hbs1-dependent manner. Translation of the poly(A) tail in NSD leads to recruitment of Ski7 and the exosome to the stalled ribosomal complex. Subsequent degradation of the mRNA body (in all three pathways) involves canonical 5’-3’ degradation by Xrn1 and 3’–5’ degradation by the exosome complex.

Figure 3. Nonsense suppression as a result of altered mRNA stability

Upper panel - Upf proteins regulate the stability of the mRNA encoding the magnesium transporter, Alr1. The uORFs in the 5’ leader of the ALR1 mRNA confer NMD sensitivity and regulate expression of the Alr1 transporter on the cell surface. This leads to normal magnesium levels in the cell, which in turn regulates the fidelity of the termination event at a premature termination codon. Lower panel - In the absence of Upf proteins, ALR1 mRNA is stabilized due to loss of NMD. Stabilization of the mRNA leads to increased expression of Alr1 protein and increased uptake of magnesium. Elevated intracellular magnesium levels affect the fidelity of translation resulting in incorporation of a near cognate tRNA at PTCs, leading to nonsense suppression.