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Ribosomal Dysfunction Is a Common Pathomechanism in Different Forms of Trichothiodystrophy
Gaojie Zhu1, Fatima Khalid1, Danhui Zhang1
1Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany.
Cells
|July 29, 2023
Summary
Trichothiodystrophy (TTD) is linked to ribosomal dysfunction. This study reveals that disrupting TTD factors impairs ribosome function, leading to protein homeostasis loss, a common mechanism in TTD.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Trichothiodystrophy (TTD) is a severe childhood disorder caused by mutations in various genes.
- TTD is classified as a DNA repair disease or a transcription syndrome involving RNA polymerase II.
Purpose of the Study:
- To identify a common underlying pathomechanism in TTD.
- To investigate the impact of TTD gene disruption on ribosomal biogenesis and function.
Main Methods:
- Knockout/knockdown of two unrelated TTD factors: TTDN1 and RNF113A.
- Analysis of RNA polymerase I transcription, rRNA processing, and protein translation quality.
Main Results:
- Disruption of TTD factors uniformly impacted RNA polymerase I transcription, downregulating UBF and disturbing rRNA processing.
- A reduction in 18S rRNA and impaired protein translation quality were observed.
- Accumulation of misfolded and carbonylated proteins indicated a loss of protein homeostasis (proteostasis).
Conclusions:
- Ribosomal dysfunction, evidenced by impaired biogenesis and protein homeostasis, is a common pathomechanism in TTD.
- These findings suggest a unified understanding of TTD pathogenesis across different genetic causes.
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