Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells

Department of Biochemistry and Biophysics, University of Rochester, School of Medicine and Dentistry, Rochester, New York, USA.
Current Opinion in Cell Biology (Impact Factor: 8.74). 07/2005; 17(3):309-15. DOI: 10.1016/
Source: PubMed

ABSTRACT Nonsense-mediated mRNA decay (NMD) generally involves nonsense codon recognition by translating ribosomes at a position approximately 25 nts upstream of a splicing-generated exon junction complex of proteins. As such, NMD provides a means to degrade abnormal mRNAs that encode potentially deleterious truncated proteins. Additionally, an estimated one-third of naturally occurring, alternatively spliced mRNAs is also targeted for NMD. Given the extraordinary frequency of alternative splicing together with data indicating that naturally occurring transcripts other than alternatively spliced mRNAs are likewise targeted for NMD, it is believed that mammalian cells routinely utilize NMD to achieve proper levels of gene expression.

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Available from: Fabrice Lejeune, Jul 31, 2015
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    • "Missense mutations constitute about 42% of all EFNB1 mutations and lead to the exchange of amino acid residues that are important for receptor-ligand interaction and signaling (Twigg et al., 2004; Wieland et al., 2005). Truncating mutations are associated with extremely reduced transcript levels via a mechanism known as nonsense-mediated RNA decay that prevents the translation of transcripts carrying PTCs (Lejeune and Maquat, 2005). Only a minority of EFNB1 truncating or splice-site mutations have been investigated at the expression level (Makarov et al., 2010; Wieland et al., 2008). "
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    ABSTRACT: Craniofrontonasal syndrome (CFNS) is an X-linked disorder caused by mutations in the EFNB1 gene and characterized by distinctive craniofacial and digital malformations. In contrast with most X-linked traits, female patients with CFNS display a more severe phenotype than males. In this report, the clinical, molecular and RNA expression analyses of a female subject with CFNS are described. A novel c.445_449delGAGGG deletion in exon 3 of EFNB1 was demonstrated in this patient. To assess the effect of this novel mutation at the transcript level, the expression of EFNB1 mRNA was studied by quantitative RT-PCR. To our knowledge, this is the first time that an EFNB1 transcript carrying a truncating mutation in exon 3 is demonstrated to undergo degradation by nonsense-mediated mRNA decay. Our results expand the mutational spectrum of CFNS and add to the functional consequences of truncating EFNB1 mutations.
    12/2014; 2:25–31. DOI:10.1016/j.mgene.2013.11.001
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    • "S6K1, when phosphorylated, also induces translation of spliced RNAs, through recruitment to the EJC (exon-junction complex) mediated by SKAR [102]. This EJC leads quality management on mRNAs, eliminating those that have PTCs (premature termination codons) (reviewed in [113]). "
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    Current Molecular Medicine 01/2014; 14(1):3-21. DOI:10.2174/1566524013666131118103706 · 3.61 Impact Factor
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    • "In other instances " unsuited " mRNAs are prevented from crossing the nuclear membrane, a selection structure which emerged in eukaryotes to separate intron-containing RNAs from the translation apparatus. In addition, other cellular systems may degrade irregularly spliced or mutated mRNAs (nonsensemediated decay, NMD) [4] [5] [6] or, eventually, altered proteins may be ubiquitinated and proteasome-degraded [7]. However , in some cases, despite all these control mechanisms, an irregular splicing or a disruption of the physiological alternative splicing may impair cell functions and bring about severe illnesses [8] [9] [10]. "
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    ABSTRACT: Conservation/mutation in the intronic initial and terminal hexanucleotides was studied in 26 orthologous cytokine receptor genes of Mouse and Human. Introns began and ended with the canonical dinucleotides GT and AG, respectively. Identical configurations were found in 57% of the 5' hexanucleotides and 28% of the 3' hexanucleotides. The actual conservation percentages of the individual variable nucleotides at each position in the hexanucleotides were determined, and the theoretical rates of conservation of groups of three nucleotides were calculated under the hypothesis of a mutual evolutionary independence of the neighboring nucleotides (random association). Analysis of the actual conservation of groups of variable nucleotides showed that, at 5', GTGAGx was significantly more expressed and GTAAGx was significantly less expressed, as compared to the random association. At 3', TTTxAG and xTGCAG were overexpressed as compared to a random association. Study of Mouse and Human transcript variants involving the splice sites showed that most variants were not inherited from the common ancestor but emerged during the process of speciation. In some variants the silencing of a terminal hexanucleotide determined skipping of the downstream exon; in other variants the constitutive splicing hexanucleotide was replaced by another potential, in-frame, splicing hexanucleotide, leading to alterations of exon lengths.
    12/2013; 2013:818954. DOI:10.1155/2013/818954
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