Abstract
Human diseases of impaired ribosome biogenesis resulting from disruption of rRNA biosynthesis or loss of ribosomal components are collectively described as ‘ribosomopathies'. Treacher Collins syndrome (TCS), a representative human ribosomopathy with craniofacial abnormalities, is attributed to mutations in the tcof1 gene that has a homologous gene called nopp140. Previous studies demonstrated that the dao-5 (dauer and aged animal overexpression gene 5) of Caenorhabditis elegans is a member of nopp140 gene family and plays a role in nucleogenesis in the early embryo. Here, we established a C. elegans model for studying Nopp140-associated ribosomopathy. A null dao-5 mutant ok542 with a semi-infertile phenotype showed a delay in gonadogenesis, as well as a higher incidence of germline apoptosis. These phenotypes in dao-5(ok542) are likely resulted from inefficient rDNA transcription that was observed by run-on analyses and chromatin immunoprecipitation (ChIP) assays measuring the RNA Pol I occupancy on the rDNA promoter. ChIP assays further showed that the modifications of acetylated histone 4 (H4Ac) and dimethylation at the lysine 9 of histone 3 (H3K9me2) around the rDNA promoter were altered in dao-5 mutants compared with the N2 wild type. In addition, activated CEP-1 (a C. elegans p53 homolog) activity was also linked to the loss of DAO-5 in terms of the transcriptional upregulation of two CEP-1 downstream effectors, EGL-1 and CED-13. We propose that the dao-5 mutant of C. elegans can be a valuable model for studying human Nopp140-associated ribosomopathy at the cellular and molecular levels.
Highlights
The etiological mutations of human Treacher Collins syndrome (TCS) are heterogeneous
Each disease results from defects in various aspects in ribosome biogenesis, for example, the mutations found in ribosomal protein genes (DBA and Schwachman–Diamond syndrome (SDS)) or the genes encoding factors associated with ribosomal DNA transcription (TCS) and ribosomal RNA processing (DKC), respectively, the resultant diseases display distinct clinical symptoms, most of which involve bone marrow failure, skeletal, and/or craniofacial defects.[3]
In addition to two reports by Hadwiger et al.[21] and Korcekova et al.,[22] in this study, we have shown that DAO-5 of Relative binding ratio a Pol l/ribosomal DNA (rDNA) promoter
Summary
The etiological mutations of human TCS are heterogeneous. Autosomal mutations in the tcof[1] gene that encodes a nucleolar protein known as Treacle provide the major link to TCS pathogenesis,[4] whereas a minority of TCS individuals with intact Treacle (8%) have recently been identified to harbor mutated POLR1D or POLR1C, the common subunits of RNA polymerase I and III.[5]. (nucleolar phosphorylated protein of 140 kD), which has as yet no human disease associated with it, could potentially be involved in ribosomopathogenesis. Nopp[140] is a highly phosphorylated protein whose tripartite organization is highly conserved and similar to Treacle (Figure 1a). Both nucleolar proteins can bind to the rDNA chromatin and participate in rDNA transcription via their C-terminal domains, respectively.[8,9] Nopp[140] was first demonstrated to be a chaperon for shuttling between the nucleolus and cytoplasm in rat liver cells.[10] Nopp[140] has . We have found that a mutant of dao-5, a C. elegans Nopp[140] homolog, exhibits severe gonadal defects because of impaired rRNA synthesis
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