CBP80-Promoted mRNP Rearrangements during the Pioneer Round of Translation, Nonsense-Mediated mRNA Decay, and Thereafter

Department of Biochemistry and Biophysics, The Center for RNA Biology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA.
Cold Spring Harbor Symposia on Quantitative Biology 03/2011; 75:127-34. DOI: 10.1101/sqb.2010.75.028
Source: PubMed


In mammalian cells, two different messenger ribonucleoproteins (mRNPs) serve as templates for protein synthesis. Newly synthesized mRNPs bound by the cap-binding protein heterodimer CBP80-CBP20 (CBC) initially undergo a pioneer round of translation. One purpose of this round of translation is to ensure the quality of gene expression, as exemplified by nonsense-mediated messenger RNA (mRNA) decay (NMD). NMD largely functions to eliminate mRNAs that prematurely terminate translation, although NMD also contributes to proper gene control, and it targets CBC-bound mRNPs. CBC-bound mRNPs are remodeled to eukaryotic translation initiation factor (eIF)4E-bound mRNPs in steps that (1) are a consequence of the pioneer round of translation and (2) occur independently of translation. Rather than supporting NMD, eIF4E-bound mRNPs provide for the bulk of cellular protein synthesis and are the primary targets of mRNA decay mechanisms that conditionally regulate gene expression. Here, we overview cellular processes by which CBC-bound mRNPs are remodeled to eIF4E-bound mRNPs. We also describe the molecular movements of certain factors during NMD in view of the influential role of CBP80.

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    • "Other MIF4G proteins may be implicated in later steps of translation initiation or its regulation (see, for example, Bolger & Wente, 2011). Complex of CBP80 and nuclear cap-binding protein CBC20 is thought to be involved in the pioneer round of translation of mRNAs (Maquat et al., 2010) exported out of the nucleus. The mRNA recruitment to ribosomes with this factor is assisted by CTIF (CBP80/20-dependent Translation Initiation Factor) and eIF3g (Choe et al., 2012; Kim et al., 2009). "
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    ABSTRACT: Abstract The conventional paradigm of translation initiation in eukaryotes states that the cap-binding protein complex eIF4F (consisting of eIF4E, eIF4G and eIF4A) plays a central role in the recruitment of capped mRNAs to ribosomes. However, a growing body of evidence indicates that this paradigm should be revised. This review summarizes the data which have been mostly accumulated in a post-genomic era owing to revolutionary techniques of transcriptome-wide analysis. Unexpectedly, these techniques have uncovered remarkable diversity in the recruitment of cellular mRNAs to eukaryotic ribosomes. These data enable a preliminary classification of mRNAs into several groups based on their requirement for particular components of eIF4F. They challenge the widely accepted concept which relates eIF4E-dependence to the extent of secondary structure in the 5' untranslated regions of mRNAs. Moreover, some mRNA species presumably recruit ribosomes to their 5' ends without the involvement of either the 5' m(7)G-cap or eIF4F but instead utilize eIF4G or eIF4G-like auxiliary factors. The long-standing concept of internal ribosome entry site (IRES)-elements in cellular mRNAs is also discussed.
    Critical Reviews in Biochemistry and Molecular Biology 02/2014; 49(2). DOI:10.3109/10409238.2014.887051 · 7.71 Impact Factor
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    • "The key NMD factor, UPF1, is an ATP-dependent RNA helicase that associates with the terminating ribosome via an interaction with eRF3 (Czaplinski et al., 1998; Kashima et al., 2006). A considerable amount of data indicate that this takes place shortly after mRNA export, while mRNA remains bound to CBC during what is termed a “pioneer” round of translation (Ishigaki et al., 2001; Maquat et al., 2010a; 2010b). Importantly the pioneer round of translation involves newly synthesized CBC-bound mRNA prior to the cytoplasmic remodeling step that replaces cap-bound CBC by eIF4E and is compatible with the observed NMD kinetics (Trcek et al., 2013 and references therein). "
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    ABSTRACT: Mammalian-cell messenger RNAs (mRNAs) are generated in the nucleus from precursor RNAs (pre-mRNAs, which often contain one or more introns) that are complexed with an array of incompletely inventoried proteins. During their biogenesis, pre-mRNAs and their derivative mRNAs are subject to extensive cis-modifications. These modifications promote the binding of distinct polypeptides that mediate a diverse array of functions needed for mRNA metabolism, including nuclear export, inspection by the nonsense-mediated mRNA decay (NMD) quality-control machinery, and synthesis of the encoded protein product. Ribonucleoprotein complex (RNP) remodeling through the loss and gain of protein constituents before and after pre-mRNA splicing, during mRNA export, and within the cytoplasm facilitates NMD, ensuring integrity of the transcriptome. Here we review the mRNP rearrangements that culminate in detection and elimination of faulty transcripts by mammalian-cell NMD.
    Moleculer Cells 01/2014; 37(1):1-8. DOI:10.14348/molcells.2014.2193 · 2.09 Impact Factor
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    • "The interaction between CRM1 and U snRNA is mediated by two adaptors, the first of which is the nuclear cap-binding complex (CBC), a heterodimeric protein complex consisting of CBP80 and CBP20 (4). CBC binds specifically to the m7G-cap structure of nascent RNA Pol II transcripts and promotes U snRNA export as well as pre-mRNA processing and pioneer-round translation [reviewed in (5,6)]. "
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    ABSTRACT: The assembly of spliceosomal U snRNPs in metazoans requires nuclear export of U snRNA precursors. Four factors, nuclear cap-binding complex (CBC), phosphorylated adaptor for RNA export (PHAX), the export receptor CRM1 and RanGTP, gather at the m(7)G-cap-proximal region and form the U snRNA export complex. Here we show that the multifunctional RNA-binding proteins p54nrb/NonO and PSF are U snRNA export stimulatory factors. These proteins, likely as a heterodimer, accelerate the recruitment of PHAX, and subsequently CRM1 and Ran onto the RNA substrates in vitro, which mediates efficient U snRNA export in vivo. Our results reveal a new layer of regulation for U snRNA export and, hence, spliceosomal U snRNP biogenesis.
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