RNA decay modulates gene expression and controls its fidelity

Abstract

Maintenance of cellular function relies on the expression of genetic information with high fidelity, a process in which RNA molecules form an important link. mRNAs are intermediates that define the proteome, rRNAs and tRNAs are effector molecules that act together to decode mRNA sequence information, and small noncoding RNAs can regulate mRNA half-life and translatability. The steady-state levels of these RNAs occur through transcriptional and posttranscriptional regulatory mechanisms, of which RNA decay pathways are integral components. RNA decay can initiate from the ends of a transcript or through endonucleolytic cleavage, and numerous factors that catalyze or promote these reactions have been identified and characterized. The rate at which decay occurs depends on RNA sequence or structural elements and usually requires the RNA to be modified in a way that allows recruitment of the decay machinery to the transcript through the binding of accessory factors or small RNAs. The major RNA decay pathways also play important roles in the quality control (QC) of gene expression. Acting in both the nucleus and cytoplasm, multiple QC factors monitor newly synthesized transcripts, or mRNAs undergoing translation, for properties essential to function, including structural integrity or the presence of complete open-reading frames. Transcripts targeted by these surveillance mechanisms are rapidly shunted into conventional decay pathways where they are degraded rapidly to ensure that they do not interfere with the normal course of gene expression. Collectively, degradative mechanisms are important determinants of the extent of gene expression and play key roles in maintaining its accuracy.

Keywords: NMD; P bodies; RNA half-life; RNA quality control; closed-loop mRNP; cytoplasmic RNA decay; decapping; exonucleolytic digestion; exosome; nuclear RNA decay; stability and instability elements.

Figure 1

a. Deadenylation-dependent mRNA decay pathways. The 3′-poly(A) tail is removed by the Ccr4–NOT or PARN deadenylases. Following deadenylation, two mechanisms can degrade the mRNA further: either decapping-dependent 5′→3′ decay or 3′→5′ exosome-mediated mRNA decay. In the 5′→3′ decay pathway, the Lsm1–7p complex associates with the 3′ end of the mRNA transcript and induces decapping by the Dcp1p/Dcp2p complex. The mRNA is then degraded by the 5′–3′ exoribonuclease, Xrn1p. Alternatively, the exosome can mediate 3′–5′ digestion of the deadenylated transcript. b. Deadenylation-independent mRNA decay pathways require recruitment of the decapping machinery. For example, in yeast, Rps28B protein interacts with Edc3p to recruit the Dcp1p/Dcp2p decapping enzyme. Following decapping, the mRNA is degraded by Xrn1p. c. Endonuclease-mediated mRNA decay involves an internal cleavage event in an mRNA, generating two fragments with unprotected ends. These fragments subsequently undergo digestion by Xrn1p or the exosome. (Adapted from reference 5).