Involvement of human ribosomal proteins in nucleolar structure and p53-dependent nucleolar stress

Nicolas, Emilien; Parisot, Pascaline; Pinto-Monteiro, Celina; Walque, Roxane de; Vleeschouwer, Christophe De; Lafontaine, Denis L. J.

doi:10.1038/ncomms11390

Cited by 173 publications

(217 citation statements)

References 56 publications

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“…For side-by-side comparisons of cells from the same tissue we employed clonal expression of transgenic Rexo5 shRNA under the hsFlp-Tubulin-GAL4 driver and examined nucleolar differences of RNAi clones compared to wild-type cells in the gut at the L3 larval stage (Figure 6A–A″, S6P,Q). Rexo5 knockdowns showed a 4-fold increase of nucleolar size compared to wild-type cells, indicative of increased ribosomal nucleolar stress (Figure 6A′″) (Boulon et al, 2010; Nicolas et al, 2016). …”

Section: Resultsmentioning

confidence: 99%

The Conserved RNA Exonuclease Rexo5 Is Required for 3′ End Maturation of 28S rRNA, 5S rRNA, and snoRNAs

et al. 2017

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SUMMARY Non-coding RNA biogenesis in higher eukaryotes has not been fully characterized. Here, we studied the Drosophila melanogaster Rexo5 (CG8368) protein, a metazoan-specific member of the DEDDh 3′-5′ single-stranded RNA exonucleases, by genetic, biochemical, and RNA sequencing approaches. Rexo5 is required for small nucleolar RNA (snoRNA) and ribosomal RNA (rRNA) biogenesis, and is essential in D. melanogaster. Loss-of-function mutants accumulate improperly 3′-end-trimmed 28S rRNA, 5S rRNA, and snoRNA precursors in vivo. Rexo5 is ubiquitously expressed at low levels in somatic metazoan cells, but extremely elevated in male and female germ cells. Loss of Rexo5 leads to increased nucleolar size, genomic instability, defective ribosome subunit export and larval death. Loss-of-germline expression compromises gonadal growth and meiotic entry during germline development.

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Section: Resultsmentioning

confidence: 99%

The Conserved RNA Exonuclease Rexo5 Is Required for 3′ End Maturation of 28S rRNA, 5S rRNA, and snoRNAs

et al. 2017

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“…1). While NPM1 silencing was not sufficient to perturb cell viability (Grisendi et al, 2005;Maggi et al, 2008) or rRNA processing (Maggi et al, 2008) in various cell lines that express WT U2AF1, NPM1 silencing has been shown to alter nucleolar shape (Nicolas et al, 2016) and the localization of ribosome biogenesis factors to the nucleolus (Castle et al, 2012). We propose increased cellular dependence on NPM1 under conditions of elevated mRNA translation such as in the presence of U2AF1-S34F.…”

Section: Discussionmentioning

confidence: 71%

Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

Akef¹,

Cappell²,

Larson³

2019

Preprint

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U2AF1 forms a heterodimeric complex with U2AF2 that is primarily responsible for 3' splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome and Acute Myeloid Leukemia, and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). However, the U2AF heterodimer also has a non-canonical function as a translational regulator. Here, we report that the U2AF1 S34F mutation results in specific mis-regulation of the translation initiation and ribosome biogenesis machinery, with the potential for widespread translational changes. The net result is a global increase in mRNA translation at the single cell level.Among the translationally upregulated targets of U2AF1-S34F are Nucleophosmin1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of wt/S34F cells and causes rRNA processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1 and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation which recapitulates translational mis-regulation in myeloid disease.

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“…They together with 5S rRNA (5S ribonucleoprotein particle, 5S RNP, rRNA in complex with proteins) inhibit Mdm2 activity and maintain the structural integrity of nucleoli (Nicolas et al 2016). 5S RNP–Mdm2–p53 pathway may be activated upon impairment of ribosome production, including downregulated RPS19 synthesis.…”

Section: A Nucleolus As An Opponent Of Cancer Cells Via P53-dependentmentioning

confidence: 99%

The nucleolus, an ally, and an enemy of cancer cells

Stępiński

2018

Histochem Cell Biol

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The rates of ribosome production by a nucleolus and of protein biosynthesis by ribosomes are tightly correlated with the rate of cell growth and proliferation. All these processes must be matched and appropriately regulated to provide optimal cell functioning. Deregulation of certain factors, including oncogenes, controlling these processes, especially ribosome biosynthesis, can lead to cell transformation. Cancer cells are characterized by intense ribosome biosynthesis which is advantageous for their growth and proliferation. On the other hand, this feature can be engaged as an anticancer strategy. Numerous nucleolar factors such as nucleolar and ribosomal proteins as well as different RNAs, in addition to their role in ribosome biosynthesis, have other functions, including those associated with cancer biology. Some of them can contribute to cell transformation and cancer development. Others, under stress evoked by different factors which often hamper function of nucleoli and thus induce nucleolar/ribosomal stress, can participate in combating cancer cells. In this sense, intentional application of therapeutic agents affecting ribosome biosynthesis can cause either release of these molecules from nucleoli or their de novo biosynthesis to mediate the activation of pathways leading to elimination of harmful cells. This review underlines the role of a nucleolus not only as a ribosome constituting apparatus but also as a hub of both positive and negative control of cancer development. The article is mainly based on original papers concerning mechanisms in which the nucleolus is implicated directly or indirectly in processes associated with neoplasia.

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Involvement of human ribosomal proteins in nucleolar structure and p53-dependent nucleolar stress

Cited by 173 publications

References 56 publications

The Conserved RNA Exonuclease Rexo5 Is Required for 3′ End Maturation of 28S rRNA, 5S rRNA, and snoRNAs

The Conserved RNA Exonuclease Rexo5 Is Required for 3′ End Maturation of 28S rRNA, 5S rRNA, and snoRNAs

Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

The nucleolus, an ally, and an enemy of cancer cells

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