Regulation of cytoplasmic mRNA decay

Department of Molecular and Cellular Biochemistry and Center for RNA Biology, The Ohio State University, Columbus, Ohio 43210, USA.
Nature Reviews Genetics (Impact Factor: 36.98). 03/2012; 13(4):246-59. DOI: 10.1038/nrg3160
Source: PubMed


Discoveries made over the past 20 years highlight the importance of mRNA decay as a means of modulating gene expression and thereby protein production. Up until recently, studies largely focused on identifying cis-acting sequences that serve as mRNA stability or instability elements, the proteins that bind these elements, how the process of translation influences mRNA decay and the ribonucleases that catalyse decay. Now, current studies have begun to elucidate how the decay process is regulated. This Review examines our current understanding of how mammalian cell mRNA decay is controlled by different signalling pathways and lays out a framework for future research.

1 Follower
54 Reads
    • "Once transcription stops at the end of the growth phase, control of gene expression becomes posttranscriptional until ZGA and involves regulation of mRNA translation, exemplified by recruitment of maternal mRNAs discussed above, and regulation of mRNA stability. mRNA degradation (reviewed in Balagopal, Fluch, & Nissan, 2012; Houseley & Tollervey, 2009; Schoenberg & Maquat, 2012) usually involves deadenylation of the 3 0 -poly(A) tail and/or decapping. In mammalian somatic cells, deadenylation coupled with decapping is the main mRNA decay pathway (Yamashita et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In mouse, the oocyte-to-embryo transition entails converting a highly differentiated oocyte to totipotent blastomeres. This transition is driven by degradation of maternal mRNAs, which results in loss of oocyte identity, and reprogramming of gene expression during the course of zygotic gene activation, which occurs primarily during the two-cell stage and confers blastomere totipotency. Full-grown oocytes are transcriptionally quiescent and mRNAs are remarkably stable in oocytes due to the RNA-binding protein MSY2, which stabilizes mRNAs, and low activity of the 5' and 3' RNA degradation machinery. Oocyte maturation initiates a transition from mRNA stability to instability due to phosphorylation of MSY2, which makes mRNAs more susceptible to the RNA degradation machinery, and recruitment of dormant maternal mRNAs that encode for critical components of the 5' and 3' RNA degradation machinery. Small RNAs (miRNA, siRNA, and piRNA) play little, if any, role in mRNA degradation that occurs during maturation. Many mRNAs are totally degraded but a substantial fraction is only partially degraded, their degradation completed by the end of the two-cell stage. Genome activation initiates during the one-cell stage, is promiscuous, low level, and genome wide (and includes both inter- and intragenic regions) and produces transcripts that are inefficiently spliced and polyadenylated. The major wave of genome activation in two-cell embryos involves expression of thousands of new genes. This unique pattern of gene expression is the product of maternal mRNAs recruited during maturation that encode for transcription factors and chromatin remodelers, as well as dramatic changes in chromatin structure due to incorporation of histone variants and modified histones.
    Current Topics in Developmental Biology 09/2015; 113:305-49. DOI:10.1016/bs.ctdb.2015.06.004 · 4.68 Impact Factor
  • Source
    • "and deadenylases (Hoefig et al., 2013; Schoenberg and Maquat, 2012). Knockdown of deadenylases and the exosome subunit EXOSC10 yielded inconsistent results in preliminary studies. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apoptosis is a tightly coordinated cell death program that damages mitochondria, DNA, proteins, and membrane lipids. Little is known about the fate of RNA as cells die. Here, we show that mRNAs, but not noncoding RNAs, are rapidly and globally degraded during apoptosis. mRNA decay is triggered early in apoptosis, preceding membrane lipid scrambling, genomic DNA fragmentation, and apoptotic changes to translation initiation factors. mRNA decay depends on mitochondrial outer membrane permeabilization and is amplified by caspase activation. 3' truncated mRNA decay intermediates with nontemplated uridylate-rich tails are generated during apoptosis. These tails are added by the terminal uridylyl transferases (TUTases) ZCCHC6 and ZCCHC11, and the uridylated transcript intermediates are degraded by the 3' to 5' exonuclease DIS3L2. Knockdown of DIS3L2 or the TUTases inhibits apoptotic mRNA decay, translation arrest, and cell death, whereas DIS3L2 overexpression enhances cell death. Our results suggest that global mRNA decay is an overlooked hallmark of apoptosis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 05/2015; 11(7). DOI:10.1016/j.celrep.2015.04.026 · 8.36 Impact Factor
  • Source
    • "To test this, we used cells isolated from FSHD1 (54-2, which are isogenic to normal 54-1 cells but carry a contracted D4Z4 array) and FSHD2 (MB200) skeletal muscle (Krom et al., 2012; Schoenberg and Maquat, 2012; Young et al., 2013). We knocked down UFP1 in 54-2 and MB200 myoblasts to 24.3% and 32.4% of normal protein levels, respectively, and differentiated these myoblasts to myotubes to stimulate DUX4 transcription. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy caused by inefficient epigenetic repression of the D4Z4 macrosatellite array and somatic expression of the DUX4 retrogene. DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when mis-expressed in skeletal muscle. The mechanism(s) of DUX4 toxicity in muscle is incompletely understood. We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates. DUX4 mRNA is itself degraded by NMD, such that inhibition of NMD by DUX4 protein stabilizes DUX4 mRNA through a double-negative feedback loop in FSHD muscle cells. This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with 'bursts' of DUX4 expression in FSHD muscle, and has implications for FSHD pathogenesis.
    eLife Sciences 01/2015; 4(4). DOI:10.7554/eLife.04996 · 9.32 Impact Factor
Show more

Similar Publications