Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany.
Medical Systems Biology, Ulm University, 89081 Ulm, Germany.
Cells. 2023 Jul 17;12(14):1877. doi: 10.3390/cells12141877.
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.
多种基因突变可引起严重的儿童疾病——毛发硫营养不良症（TTD），TTD 被归类为 DNA 修复疾病或 RNA 聚合酶 II 的转录综合征。为了确定 TTD 的常见潜在发病机制，我们敲除/敲低了两个不相关的 TTD 因子 TTDN1 和 RNF113A，并研究了它们对核糖体生物发生和功能的影响。有趣的是，干扰这些 TTD 因子对 RNA 聚合酶 I 转录产生了几乎一致的影响，导致 UBF 下调、rRNA 加工紊乱和小核糖体亚基 rRNA 18S 的骨架减少。这伴随着翻译中解码质量的降低和错误折叠和碳化蛋白质的积累，表明蛋白质平衡（蛋白质稳态）丧失。由于核糖体导致的蛋白质稳态丧失已在其他形式的 TTD 中被确定，因此我们假设核糖体功能障碍是 TTD 的常见潜在发病机制。
