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

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...

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Autores principales: Qiang, Mingyue, Khalid, Fatima, Phan, Tamara, Ludwig, Christina, Scharffetter-Kochanek, Karin, Iben, Sebastian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306422/
https://www.ncbi.nlm.nih.gov/pubmed/34203326
http://dx.doi.org/10.3390/cells10071616
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author Qiang, Mingyue
Khalid, Fatima
Phan, Tamara
Ludwig, Christina
Scharffetter-Kochanek, Karin
Iben, Sebastian
author_facet Qiang, Mingyue
Khalid, Fatima
Phan, Tamara
Ludwig, Christina
Scharffetter-Kochanek, Karin
Iben, Sebastian
author_sort Qiang, Mingyue
collection PubMed
description 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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spelling pubmed-83064222021-07-25 Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding Qiang, Mingyue Khalid, Fatima Phan, Tamara Ludwig, Christina Scharffetter-Kochanek, Karin Iben, Sebastian Cells Article 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. MDPI 2021-06-28 /pmc/articles/PMC8306422/ /pubmed/34203326 http://dx.doi.org/10.3390/cells10071616 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Qiang, Mingyue
Khalid, Fatima
Phan, Tamara
Ludwig, Christina
Scharffetter-Kochanek, Karin
Iben, Sebastian
Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding
title Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding
title_full Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding
title_fullStr Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding
title_full_unstemmed Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding
title_short Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding
title_sort cockayne syndrome-associated csa and csb mutations impair ribosome biogenesis, ribosomal protein stability, and global protein folding
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306422/
https://www.ncbi.nlm.nih.gov/pubmed/34203326
http://dx.doi.org/10.3390/cells10071616
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