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Regulation of cytoplasmic RNA stability: Lessons from Drosophila

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The process of RNA degradation is a critical level of regulation contributing to the control of gene expression. In the last two decades a number of studies have shown the specific and targeted nature of RNA decay and its importance in maintaining homeostasis. The key players within the pathways of RNA decay are well conserved with their mutation or disruption resulting in distinct phenotypes as well as human disease. Model organisms including Drosophila melanogaster have played a substantial role in elucidating the mechanisms conferring control over RNA stability. A particular advantage of this model organism is that the functions of ribonucleases can be assessed in the context of natural cells within tissues in addition to individual immortalized cells in culture. Drosophila RNA stability research has demonstrated how the cytoplasmic decay machines, such as the exosome, Dis3L2 and Xrn1, are responsible for regulating specific processes including apoptosis, proliferation, wound healing and fertility. The work discussed here has begun to identify specific mRNA transcripts that appear sensitive to specific decay pathways representing mechanisms through which the ribonucleases control mRNA stability. Drosophila research has also contributed to our knowledge of how specific RNAs are targeted to the ribonucleases including AU rich elements, miRNA targeting and 3′ tailing. Increased understanding of these mechanisms is critical to elucidating the control elicited by the cytoplasmic ribonucleases which is relevant to human disease. This article is categorized under: RNA in Disease and Development > RNA in Development RNA Turnover and Surveillance > Regulation of RNA Stability RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
Methods of targeting decay. (a) AU rich elements (AREs) usually within the 3′UTR recruit specific RNA binding proteins (Drosophila TTP homology Tis11 shown). ARE binding proteins subsequently promote 3′→5′ decay by the exosome where in Drosophila Dis3/Tazman (named Rrp44 in S. cerevisiae) provides catalytic activity or 5′→3′ decay by XRN1/Pacman (Pcm). The direction of decay can be transcript and protein specific. (b) miRNAs direct the RNA induced silencing complex (RISC) containing either Ago1 or Ago2 to specific target sites, usually in the 3′UTR, and can promote translational repression at the stages of initiation or elongation depending on the nature of the ago protein. When extensive complementarity is present between a miRNA and its target Ago2‐RISC directs cleavage of the target RNA. Extended repression can also result in mRNA degradation through classical decay pathways. (c) an mRNA can be targeted for decay following nucleotide additions to the 3′ end. Uridylation by a Drosophila terminal Uridylyl transferase (TUTase) named tailor is depicted. This primes the RNA for Dis3L2 mediated decay
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RNA Turnover and Surveillance > Regulation of RNA Stability
RNA in Disease and Development > RNA in Development
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

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