The pre-existing population of 5S rRNA effects p53 stabilization during ribosome biogenesis inhibition

Onofrillo, Carmine; Galbiati, Alice; Montanaro, Lorenzo; Derenzini, Massimo

doi:10.18632/oncotarget.13833

Cited by 11 publications

(7 citation statements)

References 28 publications

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“…WRS fibroblasts have a clear increase in pP53 expression as compared to control fibroblasts, suggesting a potential pathway of POLR3-mediated P53 regulation that is lost upon POLR3A mutation. As mentioned, the regulation of P53 is mediated in part by 5S rRNA, which is a specific POLR3 target gen (Onofrillo et al, 2017). WRS cells have a high increase of H2AX activity.…”

Section: Discussionmentioning

confidence: 93%

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts

Baez

Valencia

Velasquez

et al. 2020

Preprint

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Recently, mutations in the RNA polymerase III subunit 3A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A have important roles in the regulation of transcription of small RNAs, including tRNA, 5S rRNA and U6 snRNA. We aim to describe cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control were grown. Mutation in POLR3A causes a decreased in the expression of POLR3A mRNA and protein and a sharp increased of mutant protein.In addition, there was an increased in its nuclear localization. These changes were associated to an increase number and area of nucleoli, a significantly larger nuclear area, and a high increased in the expression of pP53 and pH2AX. All these changes were associated to premature senescence. The present observations add to our understanding of the differences between HGPS and WRS, and opens new alternatives to study cell senesce and human aging.

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Section: Discussionmentioning

confidence: 93%

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts

Baez

Valencia

Velasquez

et al. 2020

Preprint

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“…Besides MDM4, the MDM2 protein is also a target of stress signaling, and this is already known to include nucleolar stress. Not only the 5S RNP, including the ribosomal proteins L5 and L11, binds to MDM2 and prevents p53 ubiquitination (Donati et al, 2013; Onofrillo et al, 2017); other nucleolar proteins, such as nucleophosmin and perhaps even p14 ARF , move from nucleoli to nucleoplasm upon nucleolar stress, where they bind and antagonize MDM2 (Kurki et al, 2004; Llanos et al, 2001; Sherr, 2006; Yang et al, 2016). Besides the 5S RNP, additional ribosomal proteins were found in association with MDM2, including L22 (Cao et al, 2017; Liu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

The ribosomal protein L22 binds theMDM4pre-mRNA and promotes exon skipping to activate p53 upon nucleolar stress

Jansen,

Bohnsack,

Böhlken-Fascher

et al. 2023

Preprint

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The tumor suppressor p53, along with its antagonists MDM2 and MDM4, represents a central integrator of stress signaling. While DNA damage is the most widely explored trigger of a p53 response, stress can also arise from dysbalanced assembly of ribosomes in nucleoli. Deletions of the gene encoding the ribosomal protein L22 (RPL22; eL22) correlate with the presence of full-length MDM4 mRNA in human cancer, but the mechanistic basis for this phenomenon was hitherto unknown. Here we show that L22, under conditions of ribosomal and nucleolar stress, promotes the skipping of exon 6 within the MDM4 pre-mRNA. Upon L22 depletion, far more full-length MDM4 is maintained despite treatment with nucleolar stressors, leading to diminished p53 activity and enhanced proliferation. Mechanistically, L22 binds to specific RNA elements within intron 6 of MDM4 that correspond to a stem-loop consensus, leading to the skipping of exon 6. This intronic RNA overlaps with the region responsible for splice regulation by ZMAT3. Targeted deletion of these intronic elements largely abolishes L22-mediated exon skipping and re-enables cell proliferation despite nucleolar stressors such as 5-fluorouracil. L22 also governs alternative splicing of the RPL22L1 and UBAP2L mRNAs. Thus, L22 serves as a signaling intermediate that integrates different layers of gene expression. Defects in ribosome synthesis lead to specific alternative splicing, ultimately triggering p53-mediated transcription and arresting cell proliferation.

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“…uL18 and uL5 have a crucial role in the p53-dependent nucleolar stress signaling pathway, which is activated in conditions of altered ribosome biogenesis [ 28 ]. In particular, it has been demonstrated that uL18 and uL5 regulate p53 homeostasis and its activation together with 5S rRNA as part of a ribosomal subcomplex—the 5S ribonucleoprotein particle (5S RNP) [ 29 , 30 ]. Specifically, in stressed cells, uL5 translocates into the nucleoplasm and associated with the pre-existing 5S/uL18 complex to form 5S RNP that binds to MDM2, thus regulating p53 levels [ 31 ].…”

Section: Role Of Ribosome Biogenesis In Neoplastic Transformationmentioning

confidence: 99%

Ribosome Biogenesis and Cancer: Overview on Ribosomal Proteins

Pecoraro

Pagano

Russo

et al. 2021

IJMS

107

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Cytosolic ribosomes (cytoribosomes) are macromolecular ribonucleoprotein complexes that are assembled from ribosomal RNA and ribosomal proteins, which are essential for protein biosynthesis. Mitochondrial ribosomes (mitoribosomes) perform translation of the proteins essential for the oxidative phosphorylation system. The biogenesis of cytoribosomes and mitoribosomes includes ribosomal RNA processing, modification and binding to ribosomal proteins and is assisted by numerous biogenesis factors. This is a major energy-consuming process in the cell and, therefore, is highly coordinated and sensitive to several cellular stressors. In mitochondria, the regulation of mitoribosome biogenesis is essential for cellular respiration, a process linked to cell growth and proliferation. This review briefly overviews the key stages of cytosolic and mitochondrial ribosome biogenesis; summarizes the main steps of ribosome biogenesis alterations occurring during tumorigenesis, highlighting the changes in the expression level of cytosolic ribosomal proteins (CRPs) and mitochondrial ribosomal proteins (MRPs) in different types of tumors; focuses on the currently available information regarding the extra-ribosomal functions of CRPs and MRPs correlated to cancer; and discusses the role of CRPs and MRPs as biomarkers and/or molecular targets in cancer treatment.

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The pre-existing population of 5S rRNA effects p53 stabilization during ribosome biogenesis inhibition

Cited by 11 publications

References 28 publications

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts

The ribosomal protein L22 binds theMDM4pre-mRNA and promotes exon skipping to activate p53 upon nucleolar stress

Ribosome Biogenesis and Cancer: Overview on Ribosomal Proteins

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