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• W1971644927 abstract "mRNA decapping is a critical step in eukaryotic cytoplasmic mRNA turnover. Cytoplasmic mRNA decapping is catalyzed by Dcp2 in conjunction with its coactivator Dcp1 and is stimulated by decapping enhancer proteins. mRNAs associated with the decapping machinery can assemble into cytoplasmic mRNP granules called processing bodies (PBs). Evidence suggests that PB-associated mRNPs are translationally repressed and can be degraded or stored for subsequent translation. However, whether mRNP assembly into a PB is important for translational repression, decapping, or decay has remained controversial. Here, we discuss the regulation of decapping machinery recruitment to specific mRNPs and how their assembly into PBs is governed by the relative rates of translational repression, mRNP multimerization, and mRNA decay. mRNA decapping is a critical step in eukaryotic cytoplasmic mRNA turnover. Cytoplasmic mRNA decapping is catalyzed by Dcp2 in conjunction with its coactivator Dcp1 and is stimulated by decapping enhancer proteins. mRNAs associated with the decapping machinery can assemble into cytoplasmic mRNP granules called processing bodies (PBs). Evidence suggests that PB-associated mRNPs are translationally repressed and can be degraded or stored for subsequent translation. However, whether mRNP assembly into a PB is important for translational repression, decapping, or decay has remained controversial. Here, we discuss the regulation of decapping machinery recruitment to specific mRNPs and how their assembly into PBs is governed by the relative rates of translational repression, mRNP multimerization, and mRNA decay. Eukaryotic gene expression is regulated at multiple levels, including through the control of mRNA translation and degradation in the cytoplasm. Both processes are modulated by the mRNA 5′ N7-methyl guanosine (m7G) cap, which is critical for translation of most cellular mRNAs and at the same time protects them from 5′-to-3′ exonucleolytic degradation (Cougot et al., 2004bCougot N. van Dijk E. Babajko S. Seraphin B. ‘Cap-tabolism’.Trends Biochem. Sci. 2004; 29: 436-444Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). The removal of the m7G cap by the process of decapping represses gene expression by simultaneously shutting down mRNA translation and activating mRNA degradation (Eulalio et al., 2007aEulalio A. Behm-Ansmant I. Izaurralde E. P bodies: at the crossroads of post-transcriptional pathways.Nat. Rev. Mol. Cell Biol. 2007; 8: 9-22Crossref PubMed Scopus (485) Google Scholar, Parker and Sheth, 2007Parker R. Sheth U. P bodies and the control of mRNA translation and degradation.Mol. Cell. 2007; 25: 635-646Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar). The m7G cap is protected from decapping and activates translation through its association with the cytoplasmic cap-binding protein, eukaryotic initiation factor 4E (eIF4E), a component of the eIF4F complex (Cougot et al., 2004bCougot N. van Dijk E. Babajko S. Seraphin B. ‘Cap-tabolism’.Trends Biochem. Sci. 2004; 29: 436-444Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). eIF4F forms a tight complex with the mRNA cap, which is further stabilized by an interaction between the eIF4G subunit of eIF4F and cytoplasmic poly(A)-binding protein at the mRNA poly(A) tail (Amrani et al., 2008Amrani N. Ghosh S. Mangus D.A. Jacobson A. Translation factors promote the formation of two states of the closed-loop mRNP.Nature. 2008; 453: 1276-1280Crossref PubMed Scopus (61) Google Scholar, Wells et al., 1998Wells S.E. Hillner P.E. Vale R.D. Sachs A.B. Circularization of mRNA by eukaryotic translation initiation factors.Mol. Cell. 1998; 2: 135-140Abstract Full Text Full Text PDF PubMed Google Scholar). For an mRNA to be decapped, the complex between eIF4F and the mRNA cap must be antagonized by prodecapping factors. Once this occurs, translation initiation is inhibited, and mRNA decapping can ensue (Cougot et al., 2004bCougot N. van Dijk E. Babajko S. Seraphin B. ‘Cap-tabolism’.Trends Biochem. Sci. 2004; 29: 436-444Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, Eulalio et al., 2007aEulalio A. Behm-Ansmant I. Izaurralde E. P bodies: at the crossroads of post-transcriptional pathways.Nat. Rev. Mol. Cell Biol. 2007; 8: 9-22Crossref PubMed Scopus (485) Google Scholar, Parker and Sheth, 2007Parker R. Sheth U. P bodies and the control of mRNA translation and degradation.Mol. Cell. 2007; 25: 635-646Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar). Thus, mRNA decapping and mRNA translation are thought to be competing pathways. Studies over the last few years have revealed that messenger ribonucleoproteins (mRNPs) that are translationally repressed and associated with the cytoplasmic decapping machinery can concentrate in mRNP granules called processing bodies (PBs) (Eulalio et al., 2007aEulalio A. Behm-Ansmant I. Izaurralde E. P bodies: at the crossroads of post-transcriptional pathways.Nat. Rev. Mol. Cell Biol. 2007; 8: 9-22Crossref PubMed Scopus (485) Google Scholar, Parker and Sheth, 2007Parker R. Sheth U. P bodies and the control of mRNA translation and degradation.Mol. Cell. 2007; 25: 635-646Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar). However, whether PB formation plays an active role in translational repression and mRNA decay is unclear. In this review, we discuss the mechanisms by which the cytoplasmic mRNA-decapping machinery is activated on specific mRNAs and present a kinetic model that predicts the conditions under which the resulting mRNPs assemble into PBs. This kinetic model for PB formation can possibly be extended to understand the functions of other PB-like mRNP granules found in specialized cells such as neurons and germline cells. The catalytic engine of the yeast cytoplasmic mRNA-decapping machinery is composed of the catalytic subunit Dcp2 and its coactivator Dcp1. Dcp1 from the yeast Saccharomyces cerevisiae was the first identified decapping factor and was initially thought to be responsible for catalysis (LaGrandeur and Parker, 1998LaGrandeur T.E. Parker R. Isolation and characterization of Dcp1p, the yeast mRNA decapping enzyme.EMBO J. 1998; 17: 1487-1496Crossref PubMed Scopus (120) Google Scholar). However, later studies identified Dcp2 as a high-copy suppressor of temperature-sensitive yeast strains lacking functional Dcp1 (Dunckley and Parker, 1999Dunckley T. Parker R. The DCP2 protein is required for mRNA decapping in Saccharomyces cerevisiae and contains a functional MutT motif.EMBO J. 1999; 18: 5411-5422Crossref PubMed Scopus (202) Google Scholar), and bacterially expressed yeast, human, Caenorhabditis elegans, Arabidopsis thaliana, and Drosophila melanogaster Dcp2 were subsequently demonstrated to possess decapping activity in the absence of Dcp1 (Cohen et al., 2005Cohen L.S. Mikhli C. Jiao X. Kiledjian M. Kunkel G. Davis R.E. Dcp2 Decaps m2,2,7GpppN-capped RNAs, and its activity is sequence and context dependent.Mol. Cell. Biol. 2005; 25: 8779-8791Crossref PubMed Scopus (22) Google Scholar, Iwasaki et al., 2007Iwasaki S. Takeda A. Motose H. Watanabe Y. Characterization of Arabidopsis decapping proteins AtDCP1 and AtDCP2, which are essential for post-embryonic development.FEBS Lett. 2007; 581: 2455-2459Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, Lin et al., 2008Lin M.D. Jiao X. Grima D. Newbury S.F. Kiledjian M. Chou T.B. Drosophila processing bodies in oogenesis.Dev. Biol. 2008; (in press. Published online August, 2008)https://doi.org/10.1016/j.ydbio.2008.07.033Crossref Scopus (34) Google Scholar, Lykke-Andersen, 2002Lykke-Andersen J. Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay.Mol. Cell. Biol. 2002; 22: 8114-8121Crossref PubMed Scopus (210) Google Scholar, Steiger et al., 2003Steiger M. Carr-Schmid A. Schwartz D.C. Kiledjian M. Parker R. Analysis of recombinant yeast decapping enzyme.RNA. 2003; 9: 231-238Crossref PubMed Scopus (109) Google Scholar, van Dijk et al., 2002van Dijk E. Cougot N. Meyer S. Babajko S. Wahle E. Seraphin B. Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures.EMBO J. 2002; 21: 6915-6924Crossref PubMed Scopus (254) Google Scholar, Wang et al., 2002Wang Z. Jiao X. Carr-Schmid A. Kiledjian M. The hDcp2 protein is a mammalian mRNA decapping enzyme.Proc. Natl. Acad. Sci. USA. 2002; 99: 12663-12668Crossref PubMed Scopus (170) Google Scholar, Xu et al., 2006Xu J. Yang J.Y. Niu Q.W. Chua N.H. Arabidopsis DCP2, DCP1, and VARICOSE form a decapping complex required for postembryonic development.Plant Cell. 2006; 18: 3386-3398Crossref PubMed Scopus (75) Google Scholar). Other factors that catalyze decapping exist, such as DcpS, which hydrolyzes the cap product of 3′-to-5′ exonucleolytically degraded capped RNAs, the nuclear X29 decapping enzyme, and virally encoded decapping enzymes (Blanc et al., 1992Blanc A. Goyer C. Sonenberg N. The coat protein of the yeast double-stranded RNA virus L-A attaches covalently to the cap structure of eukaryotic mRNA.Mol. Cell. Biol. 1992; 12: 3390-3398Crossref PubMed Scopus (36) Google Scholar, Ghosh et al., 2004Ghosh T. Peterson B. Tomasevic N. Peculis B.A. Xenopus U8 snoRNA binding protein is a conserved nuclear decapping enzyme.Mol. Cell. 2004; 13: 817-828Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, Parrish et al., 2007Parrish S. Resch W. Moss B. Vaccinia virus D10 protein has mRNA decapping activity, providing a mechanism for control of host and viral gene expression.Proc. Natl. Acad. Sci. USA. 2007; 104: 2139-2144Crossref PubMed Scopus (33) Google Scholar, Tang et al., 2005Tang J. Naitow H. Gardner N.A. Kolesar A. Tang L. Wickner R.B. Johnson J.E. The structural basis of recognition and removal of cellular mRNA 7-methyl G ‘caps’ by a viral capsid protein: a unique viral response to host defense.J. Mol. Recognit. 2005; 18: 158-168Crossref PubMed Scopus (1) Google Scholar, Wang and Kiledjian, 2001Wang Z. Kiledjian M. Functional link between the mammalian exosome and mRNA decapping.Cell. 2001; 107: 751-762Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). However, these will not be discussed further here. The decapping reaction catalyzed by Dcp2 releases m7GDP and a 5′ monophosphorylated mRNA body. This is thought to be an irreversible process, which targets the mRNA for degradation by the 5′-to-3′ exonuclease Xrn1. Dcp2 contains an N-terminal Nudix/MutT motif, commonly found in pyrophosphatases, which is critical for decapping (Figure 1A) (Dunckley and Parker, 1999Dunckley T. Parker R. The DCP2 protein is required for mRNA decapping in Saccharomyces cerevisiae and contains a functional MutT motif.EMBO J. 1999; 18: 5411-5422Crossref PubMed Scopus (202) Google Scholar, Lykke-Andersen, 2002Lykke-Andersen J. Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay.Mol. Cell. Biol. 2002; 22: 8114-8121Crossref PubMed Scopus (210) Google Scholar, van Dijk et al., 2002van Dijk E. Cougot N. Meyer S. Babajko S. Wahle E. Seraphin B. Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures.EMBO J. 2002; 21: 6915-6924Crossref PubMed Scopus (254) Google Scholar, Wang et al., 2002Wang Z. Jiao X. Carr-Schmid A. Kiledjian M. The hDcp2 protein is a mammalian mRNA decapping enzyme.Proc. Natl. Acad. Sci. USA. 2002; 99: 12663-12668Crossref PubMed Scopus (170) Google Scholar). Like other Nudix-domain pyrophosphatases (McLennan, 2006McLennan A.G. The Nudix hydrolase superfamily.Cell. Mol. Life Sci. 2006; 63: 123-143Crossref PubMed Scopus (187) Google Scholar), the catalytic center of Dcp2 contains three conserved glutamate residues, which coordinate a divalent cation responsible for activation of a water molecule for cap hydrolysis (She et al., 2006She M. Decker C.J. Chen N. Tumati S. Parker R. Song H. Crystal structure and functional analysis of Dcp2p from Schizosaccharomyces pombe.Nat. Struct. Mol. Biol. 2006; 13: 63-70Crossref PubMed Scopus (53) Google Scholar). Biochemical studies indicate that yeast, human, and C. elegans Dcp2 can decap both m7G-capped and m2,2,7G-capped RNAs but show poor activity on unmethylated G caps (Cohen et al., 2005Cohen L.S. Mikhli C. Jiao X. Kiledjian M. Kunkel G. Davis R.E. Dcp2 Decaps m2,2,7GpppN-capped RNAs, and its activity is sequence and context dependent.Mol. Cell. Biol. 2005; 25: 8779-8791Crossref PubMed Scopus (22) Google Scholar, Piccirillo et al., 2003Piccirillo C. Khanna R. Kiledjian M. Functional characterization of the mammalian mRNA decapping enzyme hDcp2.RNA. 2003; 9: 1138-1147Crossref PubMed Scopus (69) Google Scholar, Steiger et al., 2003Steiger M. Carr-Schmid A. Schwartz D.C. Kiledjian M. Parker R. Analysis of recombinant yeast decapping enzyme.RNA. 2003; 9: 231-238Crossref PubMed Scopus (109) Google Scholar, van Dijk et al., 2002van Dijk E. Cougot N. Meyer S. Babajko S. Wahle E. Seraphin B. Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures.EMBO J. 2002; 21: 6915-6924Crossref PubMed Scopus (254) Google Scholar). Moreover, short RNAs, or RNAs hybridized to a DNA oligo at their 5′ end, are not efficiently decapped by Dcp2 in vitro (Cohen et al., 2005Cohen L.S. Mikhli C. Jiao X. Kiledjian M. Kunkel G. Davis R.E. Dcp2 Decaps m2,2,7GpppN-capped RNAs, and its activity is sequence and context dependent.Mol. Cell. Biol. 2005; 25: 8779-8791Crossref PubMed Scopus (22) Google Scholar, Piccirillo et al., 2003Piccirillo C. Khanna R. Kiledjian M. Functional characterization of the mammalian mRNA decapping enzyme hDcp2.RNA. 2003; 9: 1138-1147Crossref PubMed Scopus (69) Google Scholar, Steiger et al., 2003Steiger M. Carr-Schmid A. Schwartz D.C. Kiledjian M. Parker R. Analysis of recombinant yeast decapping enzyme.RNA. 2003; 9: 231-238Crossref PubMed Scopus (109) Google Scholar, van Dijk et al., 2002van Dijk E. Cougot N. Meyer S. Babajko S. Wahle E. Seraphin B. Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures.EMBO J. 2002; 21: 6915-6924Crossref PubMed Scopus (254) Google Scholar). These findings suggest that Dcp2 must contact the mRNA in two ways to promote efficient mRNA decapping: (1) through the m7G cap and (2) through contacts with the 5′ end of the mRNA (Figure 1A). This idea has been confirmed by recent crystallographic studies, which revealed that a conserved channel in the Dcp2 Nudix domain interacts with both the cap and the mRNA body through several important residues (Deshmukh et al., 2008Deshmukh M.V. Jones B.N. Quang-Dang D.U. Flinders J. Floor S.N. Kim C. Jemielity J. Kalek M. Darzynkiewicz E. Gross J.D. mRNA decapping is promoted by an RNA-binding channel in Dcp2.Mol. Cell. 2008; 29: 324-336Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, She et al., 2008She M. Decker C.J. Svergun D.I. Round A. Chen N. Muhlrad D. Parker R. Song H. Structural basis of dcp2 recognition and activation by dcp1.Mol. Cell. 2008; 29: 337-349Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Consequently, altering these residues results in a reduction or loss of mRNA decapping in vitro (Deshmukh et al., 2008Deshmukh M.V. Jones B.N. Quang-Dang D.U. Flinders J. Floor S.N. Kim C. Jemielity J. Kalek M. Darzynkiewicz E. Gross J.D. mRNA decapping is promoted by an RNA-binding channel in Dcp2.Mol. Cell. 2008; 29: 324-336Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, She et al., 2008She M. Decker C.J. Svergun D.I. Round A. Chen N. Muhlrad D. Parker R. Song H. Structural basis of dcp2 recognition and activation by dcp1.Mol. Cell. 2008; 29: 337-349Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Thus, it is predicted that anything associated with the cap or the immediate 5′ end of a cellular mRNA, such as the eIF4F complex, will protect the mRNA from decapping. Whereas Dcp2 exhibits decapping activity in vitro, Dcp1 is a critical Dcp2 cofactor in yeast cells (Beelman et al., 1996Beelman C.A. Stevens A. Caponigro G. LaGrandeur T.E. Hatfield L. Fortner D.M. Parker R. An essential component of the decapping enzyme required for normal rates of mRNA turnover.Nature. 1996; 382: 642-646Crossref PubMed Scopus (240) Google Scholar, Sakuno et al., 2004Sakuno T. Araki Y. Ohya Y. Kofuji S. Takahashi S. Hoshino S. Katada T. Decapping reaction of mRNA requires Dcp1 in fission yeast: its characterization in different species from yeast to human.J. Biochem. 2004; 136: 805-812Crossref PubMed Scopus (18) Google Scholar, Steiger et al., 2003Steiger M. Carr-Schmid A. Schwartz D.C. Kiledjian M. Parker R. Analysis of recombinant yeast decapping enzyme.RNA. 2003; 9: 231-238Crossref PubMed Scopus (109) Google Scholar). Moreover, recombinant yeast Dcp2 is stimulated by Dcp1, and alterations in the Dcp2 N-terminal region that impair the interaction with Dcp1 (Figure 1A) prevent efficient decapping in vitro and in vivo (Sakuno et al., 2004Sakuno T. Araki Y. Ohya Y. Kofuji S. Takahashi S. Hoshino S. Katada T. Decapping reaction of mRNA requires Dcp1 in fission yeast: its characterization in different species from yeast to human.J. Biochem. 2004; 136: 805-812Crossref PubMed Scopus (18) Google Scholar, She et al., 2004She M. Decker C.J. Sundramurthy K. Liu Y. Chen N. Parker R. Song H. Crystal structure of Dcp1p and its functional implications in mRNA decapping.Nat. Struct. Mol. Biol. 2004; 11: 249-256Crossref PubMed Scopus (54) Google Scholar, She et al., 2006She M. Decker C.J. Chen N. Tumati S. Parker R. Song H. Crystal structure and functional analysis of Dcp2p from Schizosaccharomyces pombe.Nat. Struct. Mol. Biol. 2006; 13: 63-70Crossref PubMed Scopus (53) Google Scholar, She et al., 2008She M. Decker C.J. Svergun D.I. Round A. Chen N. Muhlrad D. Parker R. Song H. Structural basis of dcp2 recognition and activation by dcp1.Mol. Cell. 2008; 29: 337-349Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, Tharun and Parker, 1999Tharun S. Parker R. Analysis of mutations in the yeast mRNA decapping enzyme.Genetics. 1999; 151: 1273-1285Crossref PubMed Google Scholar). Recent kinetic studies have provided insights into the mechanism by which Dcp1 promotes Dcp2 activity. Dcp1 strongly stimulates Dcp2 catalytic activity while having little effect on the interaction of Dcp2 with the m7G cap (Deshmukh et al., 2008Deshmukh M.V. Jones B.N. Quang-Dang D.U. Flinders J. Floor S.N. Kim C. Jemielity J. Kalek M. Darzynkiewicz E. Gross J.D. mRNA decapping is promoted by an RNA-binding channel in Dcp2.Mol. Cell. 2008; 29: 324-336Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Structural evidence suggests that this process involves the transformation of Dcp2 from an inactive open conformation to an active closed conformation, which orients the Dcp2 N terminus toward the catalytic site and renders Dcp2 catalytically active (Deshmukh et al., 2008Deshmukh M.V. Jones B.N. Quang-Dang D.U. Flinders J. Floor S.N. Kim C. Jemielity J. Kalek M. Darzynkiewicz E. Gross J.D. mRNA decapping is promoted by an RNA-binding channel in Dcp2.Mol. Cell. 2008; 29: 324-336Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, She et al., 2008She M. Decker C.J. Svergun D.I. Round A. Chen N. Muhlrad D. Parker R. Song H. Structural basis of dcp2 recognition and activation by dcp1.Mol. Cell. 2008; 29: 337-349Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). This could conceivably be an important mechanism by which Dcp2 activity is regulated in the cell. Interestingly, yeast Dcp1 interacts with Dcp2 through amino acids that are not highly conserved in metazoans (Deshmukh et al., 2008Deshmukh M.V. Jones B.N. Quang-Dang D.U. Flinders J. Floor S.N. Kim C. Jemielity J. Kalek M. Darzynkiewicz E. Gross J.D. mRNA decapping is promoted by an RNA-binding channel in Dcp2.Mol. Cell. 2008; 29: 324-336Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, She et al., 2006She M. Decker C.J. Chen N. Tumati S. Parker R. Song H. Crystal structure and functional analysis of Dcp2p from Schizosaccharomyces pombe.Nat. Struct. Mol. Biol. 2006; 13: 63-70Crossref PubMed Scopus (53) Google Scholar, She et al., 2008She M. Decker C.J. Svergun D.I. Round A. Chen N. Muhlrad D. Parker R. Song H. Structural basis of dcp2 recognition and activation by dcp1.Mol. Cell. 2008; 29: 337-349Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Moreover, human Dcp1 does not stably associate with Dcp2 in vitro or when overexpressed in human embryonic kidney (HEK) 293 cells, and human, C. elegans, and D. melanogaster Dcp1 do not stimulate Dcp2 activity in vitro (Cohen et al., 2005Cohen L.S. Mikhli C. Jiao X. Kiledjian M. Kunkel G. Davis R.E. Dcp2 Decaps m2,2,7GpppN-capped RNAs, and its activity is sequence and context dependent.Mol. Cell. Biol. 2005; 25: 8779-8791Crossref PubMed Scopus (22) Google Scholar, Fenger-Gron et al., 2005Fenger-Gron M. Fillman C. Norrild B. Lykke-Andersen J. Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping.Mol. Cell. 2005; 20: 905-915Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, Iwasaki et al., 2007Iwasaki S. Takeda A. Motose H. Watanabe Y. Characterization of Arabidopsis decapping proteins AtDCP1 and AtDCP2, which are essential for post-embryonic development.FEBS Lett. 2007; 581: 2455-2459Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, Lin et al., 2008Lin M.D. Jiao X. Grima D. Newbury S.F. Kiledjian M. Chou T.B. Drosophila processing bodies in oogenesis.Dev. Biol. 2008; (in press. Published online August, 2008)https://doi.org/10.1016/j.ydbio.2008.07.033Crossref Scopus (34) Google Scholar, Lykke-Andersen, 2002Lykke-Andersen J. Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay.Mol. Cell. Biol. 2002; 22: 8114-8121Crossref PubMed Scopus (210) Google Scholar, van Dijk et al., 2002van Dijk E. Cougot N. Meyer S. Babajko S. Wahle E. Seraphin B. Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures.EMBO J. 2002; 21: 6915-6924Crossref PubMed Scopus (254) Google Scholar). Instead, Dcp2 activity in these organisms might be stimulated through a metazoan-specific protein called Hedls/Ge-1/Edc4 (hereafter called Hedls) (Fenger-Gron et al., 2005Fenger-Gron M. Fillman C. Norrild B. Lykke-Andersen J. Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping.Mol. Cell. 2005; 20: 905-915Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, Xu et al., 2006Xu J. Yang J.Y. Niu Q.W. Chua N.H. Arabidopsis DCP2, DCP1, and VARICOSE form a decapping complex required for postembryonic development.Plant Cell. 2006; 18: 3386-3398Crossref PubMed Scopus (75) Google Scholar, Yu et al., 2005Yu J.H. Yang W.H. Gulick T. Bloch K.D. Bloch D.B. Ge-1 is a central component of the mammalian cytoplasmic mRNA processing body.RNA. 2005; 11: 1795-1802Crossref PubMed Scopus (88) Google Scholar), which in human and A. thaliana stimulates both the activity of Dcp2 and the association between Dcp2 and Dcp1 (Figure 1A) (Fenger-Gron et al., 2005Fenger-Gron M. Fillman C. Norrild B. Lykke-Andersen J. Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping.Mol. Cell. 2005; 20: 905-915Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, Xu et al., 2006Xu J. Yang J.Y. Niu Q.W. Chua N.H. Arabidopsis DCP2, DCP1, and VARICOSE form a decapping complex required for postembryonic development.Plant Cell. 2006; 18: 3386-3398Crossref PubMed Scopus (75) Google Scholar). Future studies should reveal whether Hedls is a “Dcp,” i.e., a bona fide core component of the metazoan decapping complex critical for catalysis, or an “Edc,” a more peripheral enhancer of decapping. Several lines of evidence suggest that the decapping complex competes with the cytoplasmic translation initiation eIF4F complex for the mRNA cap (Beelman and Parker, 1994Beelman C.A. Parker R. Differential effects of translational inhibition in cis and in trans on the decay of the unstable yeast MFA2 mRNA.J. Biol. Chem. 1994; 269: 9687-9692Abstract Full Text PDF PubMed Google Scholar, Schwartz and Parker, 1999Schwartz D.C. Parker R. Mutations in translation initiation factors lead to increased rates of deadenylation and decapping of mRNAs in Saccharomyces cerevisiae.Mol. Cell. Biol. 1999; 19: 5247-5256Crossref PubMed Scopus (0) Google Scholar, Schwartz and Parker, 2000Schwartz D.C. Parker R. mRNA decapping in yeast requires dissociation of the cap binding protein, eukaryotic translation initiation factor 4E.Mol. Cell. Biol. 2000; 20: 7933-7942Crossref PubMed Scopus (96) Google Scholar). Thus, the decapping of a cellular mRNP involves at least two distinct steps outlined in Figure 1B. First, the cap-binding translation factors must be displaced, and second, Dcp2 must bind the cap and catalyze decapping. Factors that stimulate decapping could potentially promote either of these steps. As the eIF4F complex is critical for translation initiation of the majority of cellular mRNAs, the first step of decapping involves the repression of mRNA translation. However, since mRNAs can be kept stably in a translationally repressed state, not all mRNAs that are translationally repressed are decapping substrates (Brengues et al., 2005Brengues M. Teixeira D. Parker R. Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies.Science. 2005; 310: 486-489Crossref PubMed Scopus (357) Google Scholar, Teixeira et al., 2005Teixeira D. Sheth U. Valencia-Sanchez M.A. Brengues M. Parker R. Processing bodies require RNA for assembly and contain nontranslating mRNAs.RNA. 2005; 11: 371-382Crossref PubMed Scopus (284) Google Scholar). The simplest hypothesis is that only the translational repression events that cause general destabilization of the eIF4F cap complex will stimulate decapping. This destabilization could conceivably be achieved by the action of prodecapping factors that either directly interfere with the eIF4F cap complex or that repress translation in a manner that, in a more indirect way, enhances the off rate of the eIF4F complex. Alternatively, decapping may occur only on those translationally repressed mRNAs that contain cis-elements that attract the decapping machinery. Several factors that accelerate decapping have been identified. These include enhancers of decapping proteins Edc1, Edc2, and Edc3, of which Edc1 and Edc2 appear to be specific to yeast, whereas Edc3 is conserved throughout eukaryotes (Figure 1A) (Cougot et al., 2004aCougot N. Babajko S. Seraphin B. Cytoplasmic foci are sites of mRNA decay in human cells.J. Cell Biol. 2004; 165: 31-40Crossref PubMed Scopus (356) Google Scholar, Dunckley et al., 2001Dunckley T. Tucker M. Parker R. Two related proteins, Edc1p and Edc2p, stimulate mRNA decapping in Saccharomyces cerevisiae.Genetics. 2001; 157: 27-37Crossref PubMed Google Scholar, Fenger-Gron et al., 2005Fenger-Gron M. Fillman C. Norrild B. Lykke-Andersen J. Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping.Mol. Cell. 2005; 20: 905-915Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, Kshirsagar and Parker, 2004Kshirsagar M. Parker R. Identification of Edc3p as an enhancer of mRNA decapping in Saccharomyces cerevisiae.Genetics. 2004; 166: 729-739Crossref PubMed Scopus (76) Google Scholar, Schwartz et al., 2003Schwartz D. Decker C.J. Parker R. The enhancer of decapping proteins, Edc1p and Edc2p, bind RNA and stimulate the activity of the decapping enzyme.RNA. 2003; 9: 239-251Crossref PubMed Scopus (45) Google Scholar). Edc1 and Edc2 show hallmarks of proteins that specifically stimulate the Dcp2 cap-binding/catalysis step (Figure 1B), because, like Dcp1 and Hedls, they stimulate decapping by Dcp2 in vitro on a naked RNA (Schwartz et al., 2003Schwartz D. Decker C.J. Parker R. The enhancer of decapping proteins, Edc1p and Edc2p, bind RNA and stimulate the activity of the decapping enzyme.RNA. 2003; 9: 239-251Crossref PubMed Scopus (45) Google Scholar, Steiger et al., 2003Steiger M. Carr-Schmid A. Schwartz D.C. Kiledjian M. Parker R. Analysis of recombinant yeast decapping enzyme.RNA. 2003; 9: 231-238Crossref PubMed Scopus (109) Google Scholar). Similarly, although no in vitro stimulation of decapping has been reported, Edc3 most likely stimulates the Dcp2 recruitment/catalysis step (Figure 1B), because cellular depletion of Edc3 impairs decapping of a subset of mRNAs, whereas no effect on translation has been reported (Badis et al., 2004Badis G. Saveanu C. Fromont-Racine M. Jacquier A. Targeted mRNA degradation by deadenylation-independent decapping.Mol. Cell. 2004; 15: 5-15Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, Coller and Parker, 2005Coller J. Parker R. General translational repression by activators of mRNA decapping.Cell. 2005; 122: 875-886Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, Kshirsagar and Parker, 2004Kshirsagar M. Parker R. Identification of Edc3p as an enhancer of mRNA decapping in Saccharomyces cerevisiae.Genetics. 2004; 166: 729-739Crossref PubMed Scopus (76) Google Scholar). Edc3 interacts directly with multiple decapping factors, including Dcp2 and Dcp1 (Figure 1A), and thus might either recruit or activate the decapping complex on target mRNAs (Decker et al., 2007Decker C.J. Teixeira D. Parker R. Edc3p and a glutamine/asparagine-rich domain of Lsm4p function in processing body assembly in Saccharomyces cerevisiae.J. Cell Biol. 2007; 179: 437-449Crossref PubMed Scopus (150) Google Scholar, Tritschler et al., 2007Tritschler F. Eulalio A. Truffault V. Hartmann M.D. Helms S. Schmidt S. Coles M. Izaurralde E. Weichenrieder O. A divergent Sm fold in EDC3 p" @default.
• W1971644927 created "2016-06-24" @default.
• W1971644927 creator A5019016423 @default.
• W1971644927 creator A5026105632 @default.
• W1971644927 date "2008-12-01" @default.
• W1971644927 modified "2023-10-12" @default.
• W1971644927 title "The Control of mRNA Decapping and P-Body Formation" @default.
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