Upf1 ATPase-Dependent mRNP Disassembly Is Required for Completion of Nonsense- Mediated mRNA Decay

Franks, Tobias M.; Singh, Guramrit; Lykke-Andersen, Jens

doi:10.1016/j.cell.2010.11.043

Cited by 206 publications

(247 citation statements)

References 69 publications

(99 reference statements)

Supporting

Mentioning

240

Contrasting

Order By: Relevance

“…1), most likely indicating that the so-called DECID complex (10) involves the 3′ UTR EJC that resides closest to the PTC. UPF1 binding to EJC-bound UPF2 increases UPF1 ATPase and helicase activities (36) to augment UPF1 movement along the mRNA 3′ UTR in a 5′-to-3′ direction (29), the concomitant removal of mRNP proteins from the mRNA, and mRNA decay (18).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the drop coincided with the accumulation of a reported 3′-degradation product of Gl Ter mRNA (18) that was evident by using cells in which the 5′-to-3′ exonuclease XRN1 was down-regulated (Fig. S2 G-I): Down-regulating XRN1 in mammalian cells has been shown to result in the accumulation of a SMG6 endonuclease-generated 3′-cleavage product of PTC-containing mRNA (16)(17)(18).…”

Section: Termination-codon Context Determines the Extent Of Upf1 Bindingmentioning

confidence: 99%

“…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). Hyperphosphorylated UPF1 then binds to eIF3 of a 43S preinitiation complex, positioned at the translation initiation codon of the NMD target, to suppress further translation initiation events (14) and promote mRNA decay (15)(16)(17)(18). One or a combination of SMG5, SMG6, and SMG7 recruits protein phosphatase 2A to return UPF1 to its steady-state hypophosphorylated status (19)(20)(21)(22).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Rules that govern UPF1 binding to mRNA 3′ UTRs

Kurosaki

Maquat

2013

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

115

120

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Termination-codon Context Determines the Extent Of Upf1 Bindingmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Rules that govern UPF1 binding to mRNA 3′ UTRs

Kurosaki

Maquat

2013

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

115

120

View full text Add to dashboard Cite

show abstract

“…Tertiary structure modeling showed extensive similarities between the helicase domains of MOV10L1 and UPF1 (Supplemental Fig. S4A-E; Supplemental Material), suggesting that MOV10L1 may use its conserved helicase core to translocate the piRNA precursor transcript, analogous to the translocation of UPF1 on mRNAs with a 5 ′ -to-3 ′ directionality (Franks et al 2010). Recently, MOV10, a ubiquitously expressed RNA helicase that has not been implicated in the piRNA pathway, was found to possess RNA-unwinding activity and assist UPF1 in mRNA degradation (Gregersen et al 2014).…”

Section: Mov10l1 Is Required For Production Of Pirna Intermediate Promentioning

confidence: 99%

The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing

et al. 2015

View full text Add to dashboard Cite

Piwi-piRNA (Piwi-interacting RNA) ribonucleoproteins (piRNPs) enforce retrotransposon silencing, a function critical for preserving the genome integrity of germ cells. The molecular functions of most of the factors that have been genetically implicated in primary piRNA biogenesis are still elusive. Here we show that MOV10L1 exhibits 5 ′ -to-3 ′ directional RNA-unwinding activity in vitro and that a point mutation that abolishes this activity causes a failure in primary piRNA biogenesis in vivo. We demonstrate that MOV10L1 selectively binds piRNA precursor transcripts and is essential for the generation of intermediate piRNA processing fragments that are subsequently loaded to Piwi proteins. Multiple analyses suggest an intimate coupling of piRNA precursor processing with elements of local secondary structures such as G quadruplexes. Our results support a model in which MOV10L1 RNA helicase activity promotes unwinding and funneling of the single-stranded piRNA precursor transcripts to the endonuclease that catalyzes the first cleavage step of piRNA processing.

show abstract

“…hUPF1 possesses RNA helicase activity that is necessary for disassembly of RNA particles, displacement of RNA-binding proteins, and efficient NMD (32,33). To determine if helicase ctivity is required for neuroprotection by hUPF1, we transfected primary rodent cortical neurons with WT or mutant TDP43-mApple and a helicase-null variant of hUPF1, hUPF1(R844C) (34), then imaged the cells using LFM (Fig.…”

Section: Superfamily-1 Helicases Exhibit Limited Neuroprotective Propmentioning

confidence: 99%

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

Barmada

Arjun

et al. 2015

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

114

164

View full text Add to dashboard Cite

Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNAbinding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43-and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders.A myotrophic lateral sclerosis (ALS) is a progressive and lethal motor neuron disease that most often arises sporadically, but can be inherited in 10-15% of patients (1). Many of the genes implicated in familial ALS (fALS) encode RNA-binding proteins, including fused in sarcoma (FUS), transactive response element DNA/RNA-binding protein of 43 kDa (TDP43), and heteronuclear ribonuclear proteins (hnRNPs) (2), emphasizing RNA-based toxicity as a fundamental mechanism contributing to motor neuron degeneration in ALS.More than 40 different mutations in the TDP43 gene (TARDBP) have now been associated with fALS (3). Disease-associated mutations in TARDBP affect the turnover (4), amount (5), and subcellular localization of TDP43 (6, 7), in many cases resulting in cytoplasmic TDP43 inclusions. Affected neurons in sporadic ALS (sALS) exhibit identical inclusions containing wild-type (WT) TDP43 (8), and WT TDP43 accumulation causes neurodegeneration in cellular and animal models (6, 9, 10), providing a pathogenic link between fALS and sALS. FUS mutations have also been linked to fALS (11,12). Unlike TDP43, FUS-related pathology is limited to fALS due to FUS mutations (13). FUS and TDP43 bind largely nonoverlapping RNA targets (14), leading to the unexpected conclusion that, despite their homology and involvement in fALS, TDP43 and FUS have distinct roles in RNA metabolism.TDP43 regulates its own expression through a negative feedback loop (15), but the mechanism by which it does so remains unclear. Conflicting data suggest that TDP43 autoregulation involves nonsense-mediated decay (NMD) (16) or exosome-mediated degradation (15). Excess TDP43 enhances splicing in the TARDBP 3′UTR, potentially targeting the transcript for NMD, whereas deficiencies in human up-frameshift prote...

show abstract

Upf1 ATPase-Dependent mRNP Disassembly Is Required for Completion of Nonsense- Mediated mRNA Decay

Cited by 206 publications

References 69 publications

Rules that govern UPF1 binding to mRNA 3′ UTRs

Rules that govern UPF1 binding to mRNA 3′ UTRs

The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

Contact Info

Product

Resources

About