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Importance and key events of prokaryotic RNA decay: the ultimate fate of an RNA molecule

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Abstract RNAs are important effectors in the process of gene expression. In bacteria, constant adaptation to environmental demands is accompanied by a continual adjustment of transcripts' levels. The cellular concentration of a given RNA is the result of the balance between its synthesis and degradation. RNA degradation is a complex process encompassing multiple pathways. Ribonucleases (RNases) are the enzymes that directly process and degrade the transcripts, regulating their amounts. They are also important in quality control of RNAs by detecting and destroying defective molecules. The rate at which RNA decay occurs depends on the availability of ribonucleases and their specificities according to the sequence and/or the structural elements of the RNA molecule. Ribosome loading and the 5′‐phosphorylation status can also modulate the stability of transcripts. The wide diversity of RNases present in different microorganisms is another factor that conditions the pathways and mechanisms of RNA degradation. RNases are themselves carefully regulated by distinct mechanisms. Several other factors modulate RNA degradation, namely polyadenylation, which plays a multifunctional role in RNA metabolism. Additionally, small non‐coding RNAs are crucial regulators of gene expression, and can directly modulate the stability of their mRNA targets. In many cases this regulation is dependent on Hfq, an RNA binding protein which can act in concert with polyadenylation enzymes and is often necessary for the activity of sRNAs. All of the above‐mentioned aspects are discussed in the present review, which also highlights the principal differences between the RNA degradation pathways for the two main Gram‐negative and Gram‐positive bacterial models. WIREs RNA 2011 2 818–836 DOI: 10.1002/wrna.94 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability

Mechanisms of RNA decay in the Gram‐negative and Gram‐positive bacterial models. (a) In E. coli the decay of the majority of transcripts starts with an endonucleolytic cleavage by RNase E. The enzyme has a preference for 5′‐monophosphorylated substrates. A possible pathway for RNase E cleavage involves a primary cleavage by the RNA pyrophosphohydrolase RppH, which converts the 5′‐triphosphorylated terminus of primary transcripts to monophosphate. However, some substrates are cleaved by RNase E regardless of the 5′‐phosphorylation status, through an alternative pathway called ‘bypass’ or ‘internal entry’, which involves the direct entry of RNase E at single‐stranded sites. RNase III is double‐stranded specific and can also initiate the decay of structured RNAs. After endonucleolytic cleavage, breakdown products are ready for exonucleolytic digestion by any of the three main exonucleases in this bacterium. Unlike RNase R, both RNase II and PNPase are sensitive to secondary structures. Exonucleolytic activity is promoted by the 3′‐polyadenylation of substrates. The activity of PAP I, the main polyadenylating enzyme in E. coli, is modulated by the RNA‐chaperone Hfq. PNPase can synthesize heteropolymeric tails that also facilitate degradation. Cycles of polyadenylation and exonucleolytic degradation have been proposed as one way to overcome secondary structures. A minor alternative pathway in the cell is the direct exonucleolytic degradation of full length transcripts (represented by a dashed arrow). Exonucleolytic degradation releases short fragments which are subsequently degraded to mononucleotides by oligoribonuclease. (b) In B. subtilis, transcripts can be degraded from the 5′‐end through the 5′–3′ exonuclease activity of RNase J1, or they can be first endonucleolytically cleaved. The 5′–3′ exonuclease activity of RNase J1 is blocked by 5′‐PPP, suggesting primary phosphate removal. The endonucleolytic cleavage can be either performed by RNase J1/RNase J2 or RNase Y. The breakdown products can be then further degraded by the 3′–5′ exonucleases, PNPase and RNase R (unprotected 3′ ends), or by the 5′–3′ exonuclease activity of RNase J1 (newly generated monophosphorylated 5′‐ends). RNase J1 is able to fully degrade its RNA substrates to mononucleotides. The final products released by RNase R and PNPase are further degraded by the oligoribonuclease homologues in B. subtilis. Here we represent ribonucleases acting independently. However some of these enzymes can act together in degradation complexes. For instance in E. coli the degradosome (RNase E, PNPase, RhlB and enolase) and in B. subtilis the putative complex formed by RNase J1/J2, RNase Y, PNPase, the RNA helicase CshA and two glycolytic enzymes.

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Structures of RNA degrading enzymes in complex with RNA substrates. On the top of the image are shown the crystal structures of endonucleases (catalytic domain of E. coli RNase E, PDB ID 2C4R, on the left; A. aeolicus RNase III, PDB ID 2NUF, on the right). The crystal structures of exonucleases are on the bottom (E. coli RNase II, PBD ID 2IX1, on the left; E. coli PNPase, PDB ID 3GCM, on the right). The crystal structure of Thermus thermophilus RNase J (PDB ID 3BK2), which has a dual function as endo‐ and exonuclease, is in the middle. RNA substrates in complex with the enzymes are colored in orange and the metal ions that assist catalysis are shown as red spheres. Purple spheres denote the Zn2+ ions important for maintenance of the principal dimers in the RNase E quarternary structure. Otherwise the colors are unrelated to the functional domains of the enzymes, but represent different protomers in the quaternary structures except in RNase II, which is active as a monomer. In this case, each color identifies a different domain (CSD1 and CSD2 are shown in cyan and light blue, respectively; S1 is shown in dark blue and the catalytic domain RDB is colored in dark cyan). A model for RNase R has been proposed but the structure is not yet available. However functional and structural data available indicates that the structure will be quite similar to RNase II. Structures were drawn using PyMOL (http://pymol.sourceforge.net).

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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Turnover and Surveillance > Regulation of RNA Stability

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