How Altered Ribosome Production Can Cause or Contribute to Human Disease: The Spectrum of Ribosomopathies

Venturi, Giulia; Montanaro, Lorenzo

doi:10.3390/cells9102300

Cited by 41 publications

(39 citation statements)

References 136 publications

(140 reference statements)

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“…Mutations in ribosomal proteins are most common in Diamond–Blackfan anemia (DBA), which is a syndrome of bone-marrow failure and elevated cancer incidence that apparently does not appear to resemble CS. However, the major difference between DBA and CS is the alteration or lack of the ribosomal proteins that might have extraribosomal functions suppressing cancer development [ 31 ]. Moreover, it has been shown that mutations in ribosomal proteins can lead to a reduced translational fidelity in DBA [ 32 ] but also in other developmental syndromes that resemble CS [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding

Qiang

Khalid

Phan

et al. 2021

Cells

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Cockayne syndrome (CS) is a developmental disorder with symptoms that are typical for the aging body, including subcutaneous fat loss, alopecia, and cataracts. Here, we show that in the cells of CS patients, RNA polymerase I transcription and the processing of the pre-rRNA are disturbed, leading to an accumulation of the 18S-E intermediate. The mature 18S rRNA level is reduced, and isolated ribosomes lack specific ribosomal proteins of the small 40S subunit. Ribosomal proteins are susceptible to unfolding and the CS cell proteome is heat-sensitive, indicating misfolded proteins and an error-prone translation process in CS cells. Pharmaceutical chaperones restored impaired cellular proliferation. Therefore, we provide evidence for severe protein synthesis malfunction, which together with a loss of proteostasis constitutes the underlying pathophysiology in CS.

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Section: Discussionmentioning

confidence: 99%

Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding

Qiang

Khalid

Phan

et al. 2021

Cells

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“…Novel techniques to quantify small changes in rRNA PTM open up new possibilities for epitranscriptomics [ 28 , 29 ], which are expected to become increasingly complex when more types of RNA PTMs can be accurately quantified [ 30 , 31 ]. New insights in ribosome heterogeneity in stem cell differentiation [ 32 ], human diseases related to single gene defects (ribosomopathies [ 33 ]), or complex multifactorial diseases such as cancer [ 34 ] underline the importance of robust reporter assays to interrogate ribosome function. As such, the ribosome is now considered a drugable target for human disease [ 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Current Practice in Bicistronic IRES Reporter Use: A Systematic Review

Akker

Zacchini

Housmans

et al. 2021

IJMS

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Bicistronic reporter assays have been instrumental for transgene expression, understanding of internal ribosomal entry site (IRES) translation, and identification of novel cap-independent translational elements (CITE). We observed a large methodological variability in the use of bicistronic reporter assays and data presentation or normalization procedures. Therefore, we systematically searched the literature for bicistronic IRES reporter studies and analyzed methodological details, data visualization, and normalization procedures. Two hundred fifty-seven publications were identified using our search strategy (published 1994–2020). Experimental studies on eukaryotic adherent cell systems and the cell-free translation assay were included for further analysis. We evaluated the following methodological details for 176 full text articles: the bicistronic reporter design, the cell line or type, transfection methods, and time point of analyses post-transfection. For the cell-free translation assay, we focused on methods of in vitro transcription, type of translation lysate, and incubation times and assay temperature. Data can be presented in multiple ways: raw data from individual cistrons, a ratio of the two, or fold changes thereof. In addition, many different control experiments have been suggested when studying IRES-mediated translation. In addition, many different normalization and control experiments have been suggested when studying IRES-mediated translation. Therefore, we also categorized and summarized their use. Our unbiased analyses provide a representative overview of bicistronic IRES reporter use. We identified parameters that were reported inconsistently or incompletely, which could hamper data reproduction and interpretation. On the basis of our analyses, we encourage adhering to a number of practices that should improve transparency of bicistronic reporter data presentation and improve methodological descriptions to facilitate data replication.

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“…Ribosomopathies are severe genetic diseases caused by mutations in genes involved in ribosome biogenesis and function and are, among others, associated with developmentally related skeletal malformations, caused by impairment of chondrogenic development of the growth plates ( Trainor and Merrill, 2014 ; Venturi and Montanaro, 2020 ). This indicates that chondrogenic differentiation is particularly susceptible to disturbances in ribosome protein translation activity.…”

Section: Discussionmentioning

confidence: 99%

Sox9 Determines Translational Capacity During Early Chondrogenic Differentiation of ATDC5 Cells by Regulating Expression of Ribosome Biogenesis Factors and Ribosomal Proteins

Caron

Eveque

Cillero‐Pastor

et al. 2021

Front. Cell Dev. Biol.

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IntroductionIn addition to the well-known cartilage extracellular matrix-related expression of Sox9, we demonstrated that chondrogenic differentiation of progenitor cells is driven by a sharply defined bi-phasic expression of Sox9: an immediate early and a late (extracellular matrix associated) phase expression. In this study, we aimed to determine what biological processes are driven by Sox9 during this early phase of chondrogenic differentiation.MaterialsSox9 expression in ATDC5 cells was knocked down by siRNA transfection at the day before chondrogenic differentiation or at day 6 of differentiation. Samples were harvested at 2 h and 7 days of differentiation. The transcriptomes (RNA-seq approach) and proteomes (Label-free proteomics approach) were compared using pathway and network analyses. Total protein translational capacity was evaluated with the SuNSET assay, active ribosomes were evaluated with polysome profiling, and ribosome modus was evaluated with bicistronic reporter assays.ResultsEarly Sox9 knockdown severely inhibited chondrogenic differentiation weeks later. Sox9 expression during the immediate early phase of ATDC5 chondrogenic differentiation regulated the expression of ribosome biogenesis factors and ribosomal protein subunits. This was accompanied by decreased translational capacity following Sox9 knockdown, and this correlated to lower amounts of active mono- and polysomes. Moreover, cap- versus IRES-mediated translation was altered by Sox9 knockdown. Sox9 overexpression was able to induce reciprocal effects to the Sox9 knockdown.ConclusionHere, we identified an essential new function for Sox9 during early chondrogenic differentiation. A role for Sox9 in regulation of ribosome amount, activity, and/or composition may be crucial in preparation for the demanding proliferative phase and subsequent cartilage extracellular matrix production of chondroprogenitors in the growth plate in vivo.

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How Altered Ribosome Production Can Cause or Contribute to Human Disease: The Spectrum of Ribosomopathies

Cited by 41 publications

References 136 publications

Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding

Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding

Current Practice in Bicistronic IRES Reporter Use: A Systematic Review

Sox9 Determines Translational Capacity During Early Chondrogenic Differentiation of ATDC5 Cells by Regulating Expression of Ribosome Biogenesis Factors and Ribosomal Proteins

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