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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MDPI AG
2021-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/7/1616 |
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| author | Mingyue Qiang Fatima Khalid Tamara Phan Christina Ludwig Karin Scharffetter-Kochanek Sebastian Iben |
| author_facet | Mingyue Qiang Fatima Khalid Tamara Phan Christina Ludwig Karin Scharffetter-Kochanek Sebastian Iben |
| author_sort | Mingyue Qiang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T04:47:09Z |
| format | Article |
| id | doaj.art-aa84fed5ff2b406ba4171afc24186d55 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T04:47:09Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-aa84fed5ff2b406ba4171afc24186d552023-12-03T13:14:08ZengMDPI AGCells2073-44092021-06-01107161610.3390/cells10071616Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein FoldingMingyue Qiang0Fatima Khalid1Tamara Phan2Christina Ludwig3Karin Scharffetter-Kochanek4Sebastian Iben5Department of Dermatology and Allergic Diseases, Ulm University, Albert-Einstein Allee 23, 89081 Ulm, GermanyDepartment of Dermatology and Allergic Diseases, Ulm University, Albert-Einstein Allee 23, 89081 Ulm, GermanyDepartment of Dermatology and Allergic Diseases, Ulm University, Albert-Einstein Allee 23, 89081 Ulm, GermanyBavarian Center for Biomedical Mass Spectrometry, TUM, University of Munich, 85354 Freising, GermanyDepartment of Dermatology and Allergic Diseases, Ulm University, Albert-Einstein Allee 23, 89081 Ulm, GermanyDepartment of Dermatology and Allergic Diseases, Ulm University, Albert-Einstein Allee 23, 89081 Ulm, GermanyCockayne 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.https://www.mdpi.com/2073-4409/10/7/1616RNA polymerase IribosomeCockayne syndrometranslational fidelityloss of proteostasis |
| spellingShingle | Mingyue Qiang Fatima Khalid Tamara Phan Christina Ludwig Karin Scharffetter-Kochanek Sebastian Iben Cockayne Syndrome-Associated CSA and CSB Mutations Impair Ribosome Biogenesis, Ribosomal Protein Stability, and Global Protein Folding Cells RNA polymerase I ribosome Cockayne syndrome translational fidelity loss of proteostasis |
| 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 | RNA polymerase I ribosome Cockayne syndrome translational fidelity loss of proteostasis |
| url | https://www.mdpi.com/2073-4409/10/7/1616 |
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