Coordinated nuclear export of 60S ribosomal subunits and NMD3 in vertebrates

Trotta, Christopher R.; Lund, Elsebet; Kahan, Lawrence; Johnson, Arlen; Dahlberg, James E.

doi:10.1093/emboj/cdg249

Cited by 122 publications

(147 citation statements)

References 52 publications

(81 reference statements)

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“…It has been shown previously that in vertebrates, the large 60 S preribosome subunit is exported via CRM1 and the transport adaptor NMD3 (40,42). We therefore investigated the role of the Nup214-Nup88 subcomplex in 60 S preribosomal nuclear export by studying the localization of GFP-tagged NMD3 (40).…”

Section: Resultsmentioning

confidence: 98%

Nup214-Nup88 Nucleoporin Subcomplex Is Required for CRM1-mediated 60 S Preribosomal Nuclear Export

Bernad¹,

Engelsma

Sanderson³

et al. 2006

Journal of Biological Chemistry

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The nuclear pore complex (NPC) conducts macromolecular transport to and from the nucleus and provides a kinetic/hydrophobic barrier composed of phenylalanine-glycine (FG) repeats. Nuclear transport is achieved through permeation of this barrier by transport receptors. The transport receptor CRM1 facilitates export of a large variety of cargoes. Export of the preribosomal 60 S subunit follows this pathway through the adaptor protein NMD3. Using RNA interference, we depleted two FG-containing cytoplasmically oriented NPC complexes, Nup214-Nup88 and Nup358, and investigated CRM1-mediated export. A dramatic defect in NMD3-mediated export of preribosomes was found in Nup214-Nup88-depleted cells, whereas only minor export defects were evident in other CRM1 cargoes or upon depletion of Nup358. We show that the large C-terminal FG domain of Nup214 is not accessible to freely diffusing molecules from the nucleus, indicating that it does not conduct 60 S preribosomes through the NPC. Consistently, derivatives of Nup214 lacking the FG-repeat domain rescued the 60 S export defect. We show that the coiled-coil region of Nup214 is sufficient for 60 S nuclear export, coinciding with recruitment of Nup88 to the NPC. Our data indicate that Nup214 plays independent roles in NPC function by participating in the kinetic/ hydrophobic barrier through its FG-rich domain and by enabling NPC gating through association with Nup88.

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Section: Resultsmentioning

confidence: 98%

Nup214-Nup88 Nucleoporin Subcomplex Is Required for CRM1-mediated 60 S Preribosomal Nuclear Export

Bernad¹,

Engelsma

Sanderson³

et al. 2006

Journal of Biological Chemistry

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“…In addition, ribosomal gene transcription is regulated through the modulation of the transcriptional apparatus and epigenetic silencing (131). Large and small mature ribosome particles are independently exported to the cytoplasm through an exportin 1 (CRM1) and Ran-GTP-dependent mechanism: export of 60S subunit requires the exchange of complexes Noc1-Noc2 by Noc3-Noc2 (102) and the association with the adaptor shuttling protein NMD3 (142), whereas the 40S needs the heterodimer Noc4p/Nop14p (103). The work by Hinsby et al exploited a machine learning-based predictor of nuclear export signals to analyze the late stage pre-40S complex, suggesting a role also for the human homolog of yeast DIM2p in the targeting and translocation of the late 40S to the cytoplasm (63).…”

Section: Structure Composition and Classical Functions Of The Nuclementioning

confidence: 99%

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Antoniali

Lirussi

Poletto

et al. 2014

Antioxidants & Redox Signaling

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Significance: An emerging concept in DNA repair mechanisms is the evidence that some key enzymes, besides their role in the maintenance of genome stability, display also unexpected noncanonical functions associated with RNA metabolism in specific subcellular districts (e.g., nucleoli). During the evolution of these key enzymes, the acquisition of unfolded domains significantly amplified the possibility to interact with different partners and substrates, possibly explaining their phylogenetic gain of functions. Recent Advances: After nucleolar stress or DNA damage, many DNA repair proteins can freely relocalize from nucleoli to the nucleoplasm. This process may represent a surveillance mechanism to monitor the synthesis and correct assembly of ribosomal units affecting cell cycle progression or inducing p53-mediated apoptosis or senescence. Critical Issues: A paradigm for this kind of regulation is represented by some enzymes of the DNA base excision repair (BER) pathway, such as apurinic/apyrimidinic endonuclease 1 (APE1). In this review, the role of the nucleolus and the noncanonical functions of the APE1 protein are discussed in light of their possible implications in human pathologies. Future Directions: A productive cross-talk between DNA repair enzymes and proteins involved in RNA metabolism seems reasonable as the nucleolus is emerging as a dynamic functional hub that coordinates cell growth arrest and DNA repair mechanisms. These findings will drive further analyses on other BER proteins and might imply that nucleic acid processing enzymes are more versatile than originally thought having evolved DNA-targeted functions after a previous life in the early RNA world. Antioxid. Redox Signal. 20, 621-639.

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“…However, terminal rRNA processing of the 18S is cytoplasmic 9 . Furthermore, results from Xenopus have suggested that processing of the 5.8S rRNA from a slightly longer pre-5.8S RNA may occur in the cytoplasm 10 , and S. pombe Eri1 is localized to the cytoplasm2. Mammalian ERI-1 localizes to the nucleolus as well as the cytoplasm 4 (Ansel et al, co-submitted).…”

Section: Online)mentioning

confidence: 99%

The exonuclease ERI-1 has a conserved dual role in 5.8S rRNA processing and RNAi

Gabel

Ruvkun

2008

Nat Struct Mol Biol

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The exonuclease ERI-1 negatively regulates RNA interference (RNAi) in Caenorhabiditis elegans and Schizosaccharomyces pombe, and is required for production of some C. elegans endogenous small-interfering RNAs. We show that ERI-1 performs 3′ end processing of the 5.8S ribosomal RNA (rRNA) in both C. elegans and S. pombe. In C. elegans, two protein isoforms of ERI-1 are localized to the cytoplasm, and each has distinct functions in rRNA processing and negative regulation of RNAi.The C. elegans eri-1 gene encodes a 3′ to 5′ exonuclease of the DEDDh superfamily of RNase T exonucleases that was identified as a negative regulator of RNA interference (RNAi) 1 . Mutations in eri-1 cause an enhanced RNA interference (Eri) phenotype by which double stranded RNAs (dsRNAs) that are ineffective in silencing target mRNAs in wildtype animals trigger robust silencing in the Eri mutant. In the fission yeast S. pombe loss of Eri1 causes increased levels of small interfering RNAs (siRNAs) corresponding to centromeric repeats and a concomitant increase in RNAi-dependent heterochromatin formation at these genomic loci 2 . Analysis of ERI-1 in C. elegans, human and fission yeast has shown that it can degrade the 3′ end of siRNAs and histone mRNAs in vitro [1][2][3][4] , but in vivo substrates for this conserved enzyme are poorly understood.In the course of the analysis of RNAs isolated from the eri-1 null mutant, we observed that the 5.8S rRNA in an eri-1 worm is longer than wild-type 5.8S rRNA (Fig. 1a). This length difference is present in all detectable 5.8S rRNA, suggesting that eri-1 mutants have an rRNA processing defect in most, if not all, cells. The mature 5.8S, 18S, and 25-28S rRNAs in eukaryotes are generated from a 35S-47S precursor RNA via a series of processing steps mediated by multiple nucleases 5 . The activity of ERI-1 as a 3′ to 5′ exonuclease [1][2][3][4] suggests that the longer 5.8S rRNA is due to an extension of the 3′ end. RNase H cleavage and 3′ end cloning on the 5.8S rRNA of wild-type and mutant C. elegans indicated that all eri-1 5.8S rRNA is at least 1 nucleotide longer than the wild-type 5.8S rRNA specifically at the 3′ end, with a substantial fraction of eri-1 5.8S rRNA containing 2 to 4 additional nucleotides ( Supplementary Fig. 1 online). The 5.8S processing defect was observed in two independently derived eri-1 alleles, including another null allele (mg388, data not shown), and is rescued by an eri-1 transgene (see below), proving that loss of eri-1 causes the 5.8S processing defect. The 5.8S processing defect was not observed in other enhanced RNAi mutants with pleiotropies in common with eri-11 ,6 (data not shown). To characterize whether ERI-1 function in rRNA trimming is an ancient feature of this orthology group, we examined the 5.8S rRNA in the S. pombe erilΔ mutant and observed a length defect similar to the C. elegans eri-1 mutant (Fig. 1b). RNase H and sequencing analysis revealed a 3′ extended 5.8S rRNA species in erilΔ containing from 2 to 8 additional 3′ nucleotides ( Supplement...

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Coordinated nuclear export of 60S ribosomal subunits and NMD3 in vertebrates

Cited by 122 publications

References 52 publications

Nup214-Nup88 Nucleoporin Subcomplex Is Required for CRM1-mediated 60 S Preribosomal Nuclear Export

Nup214-Nup88 Nucleoporin Subcomplex Is Required for CRM1-mediated 60 S Preribosomal Nuclear Export

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

The exonuclease ERI-1 has a conserved dual role in 5.8S rRNA processing and RNAi

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