The regulation of mRNA stability in mammalian cells: 2.0

Abstract

Messenger RNA decay is an essential step in gene expression to set mRNA abundance in the cytoplasm. The binding of proteins and/or noncoding RNAs to specific recognition sequences or secondary structures within mRNAs dictates mRNA decay rates by recruiting specific enzyme complexes that perform the destruction processes. Often, the cell coordinates the degradation or stabilization of functional subsets of mRNAs encoding proteins collectively required for a biological process. As well, extrinsic or intrinsic stimuli activate signal transduction pathways that modify the mRNA decay machinery with consequent effects on decay rates and mRNA abundance. This review is an update to our 2001 Gene review on mRNA stability in mammalian cells, and we survey the enormous progress made over the past decade.

Fig. 1

Messenger RNA decay pathways in mammalian cells. The deadenylation-dependent and deadenylation-independent (i.e., endonucleolytic) pathways are depicted. See text for detailed descriptions of the relevant enzymes that catalyze each decay step.

Fig. 2

Nonsense-mediated mRNA decay (NMD). During pre-mRNA splicing, EJCs deposit 20–24 nt upstream of exon-exon junctions. The mRNA exports to the cytoplasm where a pioneer round of translation begins. UPF1 is loosely bound to the CBC. If a ribosome encounters a stop codon, CBC-UPF1 promotes SMG1-UPF1 formation and binding to eRF1-eRF3 to form the SURF complex. SMG1-UPF1 binds UPF2-UPF3 within the downstream EJC, signifying the stop codon as a PTC. SMG1 phosphorylates UPF1 to recruit endoribonucleolytic and/or deadenylation/decapping enzymes, resulting in rapid mRNA degradation.

Fig. 3

Nonstop mRNA decay (NSD). Translation of mRNAs lacking a stop codon allows the ribosome to traverse the 3′-UTR and poly(A) tail and stall at the 3′-end. This leads to dissociation of PABP and mRNA degradation. The Ski7 protein binds the stalled ribosome to release the transcript and facilitate exosome-mediated 3′-5′ degradation. Decapping by Dcp1-Dcp2 and 5′-3′ degradation by Xrn1 is a minor pathway in NSD (dashed arrow), e.g., in the absence of Ski7.

Fig. 4

No-go mRNA decay (NGD). Translation stalls upon encountering a barrier to ribosome progression. The endoribonucleases Dom34 and Hbs1 bind the transcript near the stall site and initiate endonucleolytic cleavage. Exosomes and Xrn1 degrade the resulting 5′- and 3′-mRNA fragments, respectively. It is not yet known if NGD occurs in mammalian cells.

Fig. 5

Model of the interactions between Ccr4-Not subunits and GW182 for miRNA-mediated deadenylation. GW repeats, the PAM2 domain, and CIM-1/2 in GW182 are shown. Ccr4 is also known as Cnot6, and Cnot7 is also known as Caf1. Ccr4/Cnot6 and Caf1/Cnot7 are the subunits with deadenylase activity. Pan2-Pan3 are not shown. See text for additional details.