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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.
Abstract:
Mutations in a broad variety of genes can provoke the severe childhood disorder trichothiodystrophy (TTD) that is classified as a DNA repair disease or a transcription syndrome of RNA polymerase II. In an attempt to identify the common underlying pathomechanism of TTD we performed a knockout/knockdown of the two unrelated TTD factors TTDN1 and RNF113A and investigated the consequences on ribosomal biogenesis and performance. Interestingly, interference with these TTD factors created a nearly uniform impact on RNA polymerase I transcription with downregulation of UBF, disturbed rRNA processing and reduction of the backbone of the small ribosomal subunit rRNA 18S. This was accompanied by a reduced quality of decoding in protein translation and the accumulation of misfolded and carbonylated proteins, indicating a loss of protein homeostasis (proteostasis). As the loss of proteostasis by the ribosome has been identified in the other forms of TTD, here we postulate that ribosomal dysfunction is a common underlying pathomechanism of TTD.
Insights
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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