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

Cells

Christina Ludwig¹  Mingyue Qiang²  Karin Scharffetter-Kochanek²  Sebastian Iben²  Fatima Khalid²  Tamara Phan² 

[1] Bavarian Center for Biomedical Mass Spectrometry, TUM, University of Munich, 85354 Freising, Germany;Department of Dermatology and Allergic Diseases, Ulm University, Albert-Einstein Allee 23, 89081 Ulm, Germany;

关键词: RNA polymerase I;    ribosome;    Cockayne syndrome;    translational fidelity;    loss of proteostasis;   

DOI  :  10.3390/cells10071616

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown