Dyskerin depletion increases VEGF mRNA internal ribosome entry site-mediated translation
Laura Rocchi,Annalisa Pacilli,R.A. Sethi,Marianna Penzo,Robert J. Schneider,D Trerè,Maurizio Brigotti,Lorenzo Montanaro +7 more
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TLDR
A significant increase in the VEGF IRES-mediated translation after dyskerin knock-down is demonstrated, indicating for the first time that Dyskerin inhibition can upregulate the IRES translation initiation of specific mRNAs.Abstract:
Dyskerin is a nucleolar protein encoded by the DKC1 gene that (i) stabilizes the RNA component of the telomerase complex, and (ii) drives the site-specific pseudouridilation of rRNA. It is known that the partial lack of dyskerin function causes a defect in the translation of a subgroup of mRNAs containing internal ribosome entry site (IRES) elements such as those encoding for the tumor suppressors p27 and p53. In this study, we aimed to analyze what is the effect of the lack of dyskerin on the IRES-mediated translation of mRNAs encoding for vascular endothelial growth factor (VEGF). We transiently reduced dyskerin expression and measured the levels of the IRES-mediated translation of the mRNA encoding for VEGF in vitro in transformed and primary cells. We demonstrated a significant increase in the VEGF IRES-mediated translation after dyskerin knock-down. This translational modulation induces an increase in VEGF production in the absence of a significant upregulation in VEGF mRNA levels. The analysis of a list of viral and cellular IRESs indicated that dyskerin depletion can differentially affect IRES-mediated translation. These results indicate for the first time that dyskerin inhibition can upregulate the IRES translation initiation of specific mRNAs.read more
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Tuning the ribosome: The influence of rRNA modification on eukaryotic ribosome biogenesis and function
Katherine E. Sloan,Ahmed S. Warda,Sunny Sharma,Karl-Dieter Entian,Denis L. J. Lafontaine,Markus T. Bohnsack +5 more
TL;DR: Changes in the rRNA modification pattern have been observed in response to environmental changes, during development, and in disease, which suggests that rRNA modifications may contribute to the translational control of gene expression.
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The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities.
TL;DR: In this article, the occurrence of N6-methyladenosine (m6A), 5-methylcytosine(m5C) and pseudouridine (Ψ) in coding and non-coding RNAs and their physiopathological role in cancer were discussed.
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The Ribosome Biogenesis-Cancer Connection.
TL;DR: This review summarizes the research milestones regarding these relevant relationships between ribosome biogenesis and cancer.
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Hallmarks of ribosomopathies
TL;DR: The emerging hallmarks of ribosomopathies such as the appearance of ‘onco-ribosomes’ that are specialized in translating oncoproteins, dysregulation of translation-independent extra- ribosomal functions of Ribosomal proteins, rewired cellular protein and energy metabolism, and extensive oxidative stress leading to DNA damage are discussed.
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Cotranscriptional events in eukaryotic ribosome synthesis.
TL;DR: This review will focus on the many and complex interactions occurring during pre‐rRNA synthesis, particularly in budding yeast in which the pathway is best understood.
References
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A telomerase component is defective in the human disease dyskeratosis congenita
TL;DR: It is found that primary fibroblasts and lymphoblasts from DKC-affected males are not detectably deficient in conventional H/ACA small nucleolar RNA accumulation or function; however, DKC cells have a lower level of telomerase RNA, produce lower levels of telomersase activity and have shorter telomeres than matched normal cells.
Journal ArticleDOI
X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions
Nina S. Heiss,Stuart W. Knight,Tom Vulliamy,Sabine M. Klauck,Stefan Wiemann,Philip J. Mason,Annemarie Poustka,Inderjeet Dokal +7 more
TL;DR: Five different missense mutations in five unrelated patients were subsequently identified in XAP101, indicating that it is the gene responsible for X-linked DKC (DKC1), which is the orthologue of rat NAP57 and Saccharomyces cerevisiae CBF5.
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