UPF1 Association with the Cap-Binding Protein, CBP80, Promotes Nonsense-Mediated mRNA Decay at Two Distinct Steps

Hwang, Jungwook; Sato, Hanae; Tang, Yali; Matsuda, Daiki; Maquat, Lynne E.

doi:10.1016/j.molcel.2010.07.004

Cited by 106 publications

(119 citation statements)

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“…the PTC as part of the SURF complex via its interaction with eRF3, which is promoted by the interaction of UPF1 with CBP80 (12). UPF1 then loads onto the 3′ UTRs of mRNAs beginning ≥35 nt downstream of the PTC (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we follow up our finding that human UPF1 binds an order of magnitude more efficiently to a PTC-containing mRNA than to its PTC-free counterpart (12) with the goal of defining rules that would predict the extent and position of UPF1 binding to mammalian-cell mRNAs. Although NMD requires translation, the translational dependence of UPF1 binding to mRNA 3′ UTRs remains controversial (28,29).…”

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confidence: 93%

“…Read-through therapies have shown promise in generating full-length proteins without concomitantly stabilizing PTC-bearing mRNAs (26,27). However, a deeper understanding of how such transcripts are recognized and selectively degraded by NMD is needed considering that UPF1 has been reported to bind to many mammalian mRNAs regardless of PTC status (12,28).Here, we follow up our finding that human UPF1 binds an order of magnitude more efficiently to a PTC-containing mRNA than to its PTC-free counterpart (12) with the goal of defining rules that would predict the extent and position of UPF1 binding to mammalian-cell mRNAs. Although NMD requires translation, the translational dependence of UPF1 binding to mRNA 3′ UTRs remains controversial (28,29).…”

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confidence: 99%

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confidence: 99%

“…When translation terminates at a PTC and an EJC is situated sufficiently downstream of the PTC so as not to be displaced by the terminating ribosome (8,9), a complex called suppressor with morphogenic effect on genitalia (SMG) 1−upframeshift 1 (UPF1)−eukaryotic release factor (eRF) 1−eRF3 (SURF) is thought to form at the PTC and, together with the downstream EJC, constitutes a decay-inducing complex (DECID) (10,11). The transient and/or weak interaction of mRNA capbound CBP80 with UPF1, which occurs on mRNAs even if they are not NMD targets, promotes UPF1 binding to eRF1−eRF3 and, subsequently, to an EJC (12). Although SMG8 and SMG9 tightly associate with SMG1 to suppress its kinase activity (11,13), the EJC constituents UPF2 and UPF3 or UPF3X (also called UPF3a or UPF3b, respectively) augment the SMG1-mediated phosphorylation of UPF1 (10).…”

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Rules that govern UPF1 binding to mRNA 3′ UTRs

Kurosaki

Maquat

2013

Proc. Natl. Acad. Sci. U.S.A.

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Nonsense-mediated mRNA decay (NMD), which degrades transcripts harboring a premature termination codon (PTC), depends on the helicase up-frameshift 1 (UPF1). However, mRNAs that are not NMD targets also bind UPF1. What governs the timing, position, and function of UPF1 binding to mRNAs remains unclear. We provide evidence that (i) multiple UPF1 molecules accumulate on the 3′-untranslated region (3′ UTR) of PTC-containing mRNAs and to an extent that is greater per unit 3′ UTR length if the mRNA is an NMD target; (ii) UPF1 binding begins ≥35 nt downstream of the PTC; (iii) enhanced UPF1 binding to the 3′ UTR of PTC-containing mRNA relative to its PTC-free counterpart depends on translation; and (iv) the presence of a 3′ UTR exon-junction complex (EJC) further enhances UPF1 binding and/or affinity. Our data suggest that NMD involves UPF1 binding along a 3′ UTR whether the 3′ UTR contains an EJC. This binding explains how mRNAs without a 3′ UTR EJC but with an abnormally long 3′ UTR can be NMD targets, albeit not as efficiently as their counterparts that contain a 3′ UTR EJC.messenger ribonucleoprotein structure | RNA-binding protein | messenger RNA quality control I n mammalian cells, mRNAs and the pre-mRNAs from which they derive continually lose and acquire proteins in ways that reflect past and current metabolic states and influence future metabolic steps. For example, newly synthesized mRNAs, which support the pioneer round of translation, are bound by the capbinding protein (CBP) heterodimer CBP80−CBP20 and, provided they underwent splicing, exon-junction complexes (EJCs) (1). In contrast, the bulk of cellular mRNAs have lost CBP80−CBP20 and EJCs, have acquired eukaryotic translation initiation factor (eIF)4E in the place of CBP80−CBP20, and support most of cellular translation. CBP80 and EJCs are important for nonsensemediated mRNA decay (NMD), which down-regulates mRNAs that harbor either an exon-exon junction downstream of a termination codon (2, 3) and/or an abnormally long 3′ UTR (3-6). Thus, NMD targets newly synthesized mRNAs during the pioneer round of translation, whereas eIF4E-bound mRNAs appear to be immune to NMD (1, 3). This conclusion is supported by single-RNA fluorescent in situ-hybridization measurements of premature termination codon (PTC)-containing mRNAs in intact cells after the induction of mRNA synthesis (7).Messenger ribonucleoprotein (mRNP) remodeling also takes place during NMD. When translation terminates at a PTC and an EJC is situated sufficiently downstream of the PTC so as not to be displaced by the terminating ribosome (8, 9), a complex called suppressor with morphogenic effect on genitalia (SMG) 1−upframeshift 1 (UPF1)−eukaryotic release factor (eRF) 1−eRF3 (SURF) is thought to form at the PTC and, together with the downstream EJC, constitutes a decay-inducing complex (DECID) (10, 11). The transient and/or weak interaction of mRNA capbound CBP80 with UPF1, which occurs on mRNAs even if they are not NMD targets, promotes UPF1 binding to eRF1−eRF3 and, subsequently, to an EJC (12...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Rules that govern UPF1 binding to mRNA 3′ UTRs

Kurosaki

Maquat

2013

Proc. Natl. Acad. Sci. U.S.A.

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115

120

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C ap ‐b inding complex (CBC)

2015

The Dictionary of Genomics, Transcriptomics and Proteomics

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The 7mG (7-methylguanosine cap) formed on mRNA is fundamental to eukaryotic gene expression. Protein complexes recruited to 7mG mediate key processing events throughout the lifetime of the transcript. One of the most important mediators of 7mG functions is CBC (cap-binding complex). CBC has a key role in several gene expression mechanisms, including transcription, splicing, transcript export and translation. Gene expression can be regulated by signalling pathways which influence CBC function. The aim of the present review is to discuss the mechanisms by which CBC mediates and co-ordinates multiple gene expression events.

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A novel homozygous KCNQ3 loss‐of‐function variant causes non‐syndromic intellectual disability and neonatal‐onset pharmacodependent epilepsy

et al. 2019

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Objective Heterozygous variants in KCNQ2 or, more rarely, KCNQ3 genes are responsible for early‐onset developmental/epileptic disorders characterized by heterogeneous clinical presentation and course, genetic transmission, and prognosis. While familial forms mostly include benign epilepsies with seizures starting in the neonatal or early‐infantile period, de novo variants in KCNQ2 or KCNQ3 have been described in sporadic cases of early‐onset encephalopathy (EOEE) with pharmacoresistant seizures, various age‐related pathological EEG patterns, and moderate/severe developmental impairment. All pathogenic variants in KCNQ2 or KCNQ3 occur in heterozygosity. The aim of this work was to report the clinical, molecular, and functional properties of a new KCNQ3 variant found in homozygous configuration in a 9‐year‐old girl with pharmacodependent neonatal‐onset epilepsy and non‐syndromic intellectual disability. Methods Exome sequencing was used for genetic investigation. KCNQ3 transcript and subunit expression in fibroblasts was analyzed with quantitative real‐time PCR and Western blotting or immunofluorescence, respectively. Whole‐cell patch‐clamp electrophysiology was used for functional characterization of mutant subunits. Results A novel single‐base duplication in exon 12 of KCNQ3 (NM_004519.3:c.1599dup) was found in homozygous configuration in the proband born to consanguineous healthy parents; this frameshift variant introduced a premature termination codon (PTC), thus deleting a large part of the C‐terminal region. Mutant KCNQ3 transcript and protein abundance was markedly reduced in primary fibroblasts from the proband, consistent with nonsense‐mediated mRNA decay. The variant fully abolished the ability of KCNQ3 subunits to assemble into functional homomeric or heteromeric channels with KCNQ2 subunits. Significance The present results indicate that a homozygous KCNQ3 loss‐of‐function variant is responsible for a severe phenotype characterized by neonatal‐onset pharmacodependent seizures, with developmental delay and intellectual disability. They also reveal difference in genetic and pathogenetic mechanisms between KCNQ2 ‐ and KCNQ3 ‐related epilepsies, a crucial observation for patients affected with EOEE and/or developmental disabilities.

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UPF1 Association with the Cap-Binding Protein, CBP80, Promotes Nonsense-Mediated mRNA Decay at Two Distinct Steps

Cited by 106 publications

References 65 publications

Rules that govern UPF1 binding to mRNA 3′ UTRs

Rules that govern UPF1 binding to mRNA 3′ UTRs

C ap ‐b inding complex (CBC)

A novel homozygous KCNQ3 loss‐of‐function variant causes non‐syndromic intellectual disability and neonatal‐onset pharmacodependent epilepsy

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