The human intronless melanocortin 4-receptor gene is NMD insensitive

Brocke, Katja S.; Neu‐Yilik, Gabriele; Gehring, Niels H.; Hentze, Matthias W.; Kulozik, Andreas E.

doi:10.1093/hmg/11.3.331

Cited by 70 publications

(47 citation statements)

References 44 publications

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“…The anti-sense orientation, or a mutated RSE sequence, did not stabilize the RNA. These findings differ from previous observations in higher eukaryotic cells showing that unspliced RNA does not undergo NMD and that a downstream EJC triggers NMD (Le Hir et al 2000a;Lykke-Andersen et al 2000;Maquat and Li 2001;Brocke et al 2002). We hypothesize that, in chicken cells, the RSE promotes proper translation termination of the viral RNA when next to a termination codon, and in its absence, NMD occurs.…”

Section: Discussioncontrasting

confidence: 99%

“…In mammalian cells, a mark deposited by a prior splicing event downstream of a termination codon appears to signal premature termination. Thus, an RNA without an intron downstream of a PTC should be immune to NMD (Maquat and Li 2001;Brocke et al 2002). However, a loosely characterized ''failsafe signal'' in globin mRNA acts to direct NMD even in the absence of a downstream intron (Zhang et al 1998b).…”

Section: Different Organisms Have Developed Alternative Mechanisms Ofmentioning

confidence: 99%

“…In turn, naturally intronless genes are immune to NMD in mammalian cells (Maquat and Li 2001;Brocke et al 2002).…”

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confidence: 99%

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A 3′ UTR sequence stabilizes termination codons in the unspliced RNA of Rous sarcoma virus

Weil

Beemon²

2005

RNA

106

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Eukaryotic cells target mRNAs to the nonsense-mediated mRNA decay (NMD) pathway when translation terminates within the coding region. In mammalian cells, this is presumably due to a downstream signal deposited during pre-mRNA splicing. In contrast, unspliced retroviral RNA undergoes NMD in chicken cells when premature termination codons (PTCs) are present in the gag gene. Surprisingly, deletion of a 401-nt 3¢ UTR sequence immediately downstream of the normal gag termination codon caused this termination event to be recognized as premature. We termed this 3¢ UTR region the Rous sarcoma virus (RSV) stability element (RSE). The RSE also stabilized the viral RNA when placed immediately downstream of a PTC in the gag gene. Deletion analysis of the RSE indicated a smaller functional element. We conclude that this 3¢ UTR sequence stabilizes termination codons in the RSV RNA, and termination codons not associated with such an RSE sequence undergo NMD.

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Section: Discussioncontrasting

confidence: 99%

Section: Different Organisms Have Developed Alternative Mechanisms Ofmentioning

confidence: 99%

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A 3′ UTR sequence stabilizes termination codons in the unspliced RNA of Rous sarcoma virus

Weil

Beemon²

2005

RNA

106

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“…If translation terminates at an NC that resides more than 50-55 nucleotides upstream of an exon-exon junction, then Upf1 is thought to elicit NMD by interacting with EJCassociated Upf2 (Maquat, 2004a;LykkeAndersen et al, 2000;Mendell et al, 2000;Serin et al, 2001). Consistent with a role for EJCs in NMD is the observation that NC-containing mRNAs that derive from intronless genes fail to undergo NMD (Brocke et al, 2002;Maquat and Li, 2001).…”

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confidence: 73%

Nonsense-mediated mRNA decay in mammals

Maquat

2005

Journal of Cell Science

245

217

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In mammals, two different messenger ribonucleoproteins (mRNPs) serve as templates for protein synthesis. Newly synthesized CBP80‐CBP20 (CBC)‐bound mRNPs initially undergo a pioneer round of translation (Maquat et al., 2010). One purpose of this round is to ensure the quality of gene expression, as exemplified by nonsense‐mediated mRNA decay (NMD). NMD functions to eliminate mRNAs that prematurely terminate translation, and also contributes to proper gene control, and it targets CBC‐bound mRNPs (Sato et al., 2008; Isken et al., 2008). CBC‐bound mRNPs are remodeled to eIF4E‐bound mRNPs as a consequence of the pioneer round of translation and also independently of translation (Sato & Maquat, 2009). eIF4E‐bound mRNPs support the bulk of cellular protein synthesis and are the primary targets of mRNA decay mechanisms that conditionally regulate gene expression, such as Staufen1‐mediated mRNA decay (SMD) (Gong et al., 2009). Mechanistic aspects of NMD will be discussed, including how CBP80, which is acquired by the 5′ caps of newly synthesized transcripts, promotes NMD at multiple steps by promoting specific mRNP rearrangements (Hwang et al., 2010). Mechanistic aspects of SMD will also be described, including how Staufen1‐binding sites form not only by intramolecular base‐pairing within an mRNA 3′‐untranslated region but also by intermolecular basepairing between the Alu element of an mRNA 3‐untranslated region and a partially complementary Alu element within a long noncoding RNA (Gong & Maquat, 2011).

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“…Mechanistically, the activation of NMD by nonsense mutations has been related to the interaction between the translation termination complex and a downstream exon junction complex (EJC), a situation that cannot arise with nonsense mutations in the 39-terminal exon, thus explaining the failure of such mutations to activate NMD (for review, see Maquat 2004;Neu-Yilik and Kulozik 2008;Shyu et al 2008;Rebbapragada and Lykke-Andersen 2009;Nicholson et al 2010). The dependence of NMD on nuclear splicing is confirmed by the observation that most naturally or artificially intronless genes are resistant to NMD (Maquat and Li 2001;Neu-Yilik et al 2001;Brocke et al 2002). Recently, splicing-independent and EJC-independent examples of human NMD have also been described.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon

Neu‐Yilik

Amthor²,

Gehring³

et al. 2011

RNA

119

105

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The degradation of nonsense-mutated b-globin mRNA by nonsense-mediated mRNA decay (NMD) limits the synthesis of C-terminally truncated dominant negative b-globin chains and thus protects the majority of heterozygotes from symptomatic b-thalassemia. b-globin mRNAs with nonsense mutations in the first exon are known to bypass NMD, although current mechanistic models predict that such mutations should activate NMD. A systematic analysis of this enigma reveals that (1) b-globin exon 1 is bisected by a sharp border that separates NMD-activating from NMD-bypassing nonsense mutations and (2) the ability to bypass NMD depends on the ability to reinitiate translation at a downstream start codon. The data presented here thus reconcile the current mechanistic understanding of NMD with the observed failure of a class of nonsense mutations to activate this important mRNA quality-control pathway. Furthermore, our data uncover a reason why the position of a nonsense mutation alone does not suffice to predict the fate of the affected mRNA and its effect on protein expression.

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The human intronless melanocortin 4-receptor gene is NMD insensitive

Cited by 70 publications

References 44 publications

A 3′ UTR sequence stabilizes termination codons in the unspliced RNA of Rous sarcoma virus

A 3′ UTR sequence stabilizes termination codons in the unspliced RNA of Rous sarcoma virus

Nonsense-mediated mRNA decay in mammals

Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon

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