Mutations of EXOSC3/Rrp40p associated with neurological diseases impact ribosomal RNA processing functions of the exosome in S. cerevisiae
Open accessAbstract
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.
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The RNA exosome plays central roles in ribosomal RNA processing (rRNA) and defects in rRNA processing have been identified in yeast and fly models expressing EXOSC3 variants.
“The RNA exosome also plays central roles in ribosomal RNA processing (rRNA) and defects in rRNA processing have been identified in yeast and fly models expressing EXOSC3 variants15,48.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [48]
The Introduction identifies pre-rRNA processing as a major exosome function, and the Abstract reports defective pre-rRNA processing in yeast expressing EXOSC3/Rrp40p variants. This paper does not report an EXOSC3-variant fly model, so it supports the yeast portion but not the fly portion of the cited sentence. (LLM, conf=0.88)
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The RNA exosome maintains cellular RNA homeostasis by controlling transcript abundance in the brain
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Self-citationEXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery
Wijeratne, H. R. S., Runnebohm, A. M., Barron, M. P., Hampton, A. J., Li, R., Peck Justice, S. A., Lenceski, S. H., Rooney, J. D., Smith-Kinnaman, W. R., Chang, G. S., et al. (2026) · doi:10.64898/2026.01.26.701775 · Cited by 1 · see citing works
- Authors
- Gillespie, A., Gabunilas, J., Jen, J. C., & Chanfreau, G. F.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- RNA
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-01-04
- Volume
- 23
- Issue
- 4
- Pages
- 466-472
- ISSN
- 1355-8382 (ISSN-L)
- 1469-9001
- PMC
- PMC5340910
- OpenAlex
- W2568408493
- Cited by
- 35
- References
- 1
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 3
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- RNA (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R01 GM61518, T32GM007185)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- EXOSC3, RNA exosome, pontocerebellar hypoplasia, motor neuron degeneration, pre-rRNA processing, ribosome biogenesis, conserved residues, yeast model
- MeSH terms
- Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Amino Acid Sequence, Binding Sites, Humans, Mutation, Olivopontocerebellar Atrophies, Protein Binding, RNA Precursors, RNA Processing, Post-Transcriptional, RNA, Fungal, RNA, Ribosomal, Saccharomyces cerevisiae, Gene Expression Regulation, Fungal, Sequence Alignment, RNA-Binding Proteins, Conserved Sequence, Sequence Homology, Amino Acid, Amino Acid Substitution, Saccharomyces cerevisiae Proteins, Protein Interaction Domains and Motifs, Exosome Multienzyme Ribonuclease Complex
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