Ribosomal Dysfunction Is a Common Pathomechanism in Different Forms of Trichothiodystrophy

卷:12

Article

关键词: UV-SENSITIVE SYNDROME;    C7ORF11 TTDN1 GENE;    COCKAYNE-SYNDROME;    MUTATIONS;    TFIIH;    TRANSCRIPTION;    DEFECTS;    PATIENT;    UBTF;   

DOI  :  10.3390/cells12141877

来源: SCIE

【 摘 要 】

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.