Abstract
The RNA exosome is a conserved multiprotein complex that achieves a large number of processive and degradative functions in eukaryotic cells. Recently, mutations have been mapped to the gene encoding one of the subunits of the exosome, EXOSC3 (yeast Rrp40p), which results in pontocerebellar hypoplasia with motor neuron degeneration in human patients. However, the molecular impact of these mutations in the pathology of these diseases is not well understood. To investigate the molecular consequences of mutations in EXOSC3 that lead to neurological diseases, we analyzed the effect of three of the mutations that affect conserved residues of EXOSC3/Rrp40p (G31A, G191C, and W238R; G8A, G148C, and W195R, respectively, in human and yeast) in S. cerevisiae. We show that the severity of the phenotypes of these mutations in yeast correlate with that of the disease in human patients, with the W195R mutant showing the strongest growth and RNA processing phenotypes. Furthermore, we show that these mutations affect more severely pre-ribosomal RNA processing functions of the exosome rather than other nuclear processing or surveillance functions. These results suggest that delayed or defective pre-rRNA processing might be the primary defect responsible for the pathologies detected in patients with mutations affecting EXOSC3 function in residues conserved throughout eukaryotes.
Highlights
The RNA exosome is a multiprotein complex first identified in S. cerevisiae (Mitchell et al 1997) and conserved in eukaryotic cells (Allmang et al 1999b)
The W195R mutation (EXOSC3 W238R) exhibits the most severe growth phenotype when introduced into Rrp40p
To gain further insights into the potential mechanisms by which EXOSC3 mutations cause PCH1B and related disorders, we introduced some of these mutations into the S. cerevisiae homolog of
Summary
The RNA exosome is a multiprotein complex first identified in S. cerevisiae (Mitchell et al 1997) and conserved in eukaryotic cells (Allmang et al 1999b). In addition to these processing functions, the nuclear exosome of S. cerevisiae degrades a large number of cryptic transcripts or precursor species (Kadaba et al 2004; Wyers et al 2005; Gudipati et al 2012) and is involved in the quality control of gene expression by degrading unspliced RNAs in the nucleus (BousquetAntonelli et al 2000; Sayani and Chanfreau 2012).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
