# A Budding Yeast Model for Human Disease-Mutations in the RNA Exosome

> **NIH NIH F31** · EMORY UNIVERSITY · 2020 · $45,520

## Abstract

PROJECT SUMMARY:
The RNA exosome, an essential molecular machine that contributes to processing and/or decay of nearly every
species of RNA, is a multi-subunit complex that is conserved across all eukaryotes in both sequence and
structure. Recently, mutations have been identified in genes that encode structural subunits of the RNA
exosome. Although these mutations all occur in genes that encode components of the same complex, they cause
distinct, tissue specific human disease, including neurodegenerative diseases and developmental disorders.
This growing collection of RNA exosome-linked diseases can be classified as “exosomopathies”. The disease-
causing mutations are missense mutations that alter single amino acids in conserved regions of these structural
subunits. Explaining the tissue-specific nature of these diseases is challenging if the amino acid substitutions
generally affect the molecular function(s) of this complex. Rather, the different amino acid substitutions could
have distinct consequences that differentially affect key interactions and/or the integrity of the complex, ultimately
disrupting RNA targeting/processing. I hypothesize that distinct disease-causing amino acid substitutions
differentially impact the function of the RNA exosome. The studies proposed here will compare the in vivo
consequences of two exosomopathy mutations identified in the structural subunit genes EXOSC2 and EXOSC5
(identified by our clinical collaborator), using Saccharomyces cerevisiae. Mutations in EXOSC5 are linked to
cerebellar degeneration, while mutations in EXOSC2 are linked to a novel syndrome characterized by retinitis
pigmentosa, hearing loss, premature aging and mild intellectual disability. We have already generated S.
cerevisiae models for each of these disease-linked amino acid substitutions: EXOSC2 amino acid substitution,
G226D in the yeast orthologue Rrp4, and the disease-linked EXOSC5 amino acid substitution, L191H in the
yeast orthologue Rrp45. Each of these amino acid substitutions causes a temperature sensitive growth defect
that can be exploited in yeast genetics approaches. Importantly, my preliminary data reveal that these mutations
are differentially suppressed by overexpression of distinct RNA exosome cofactors, factors that interact with the
complex to confer target specificity. These preliminary data suggest distinct in vivo consequences for these two
mutations, illustrating the importance and value of studying the molecular underpinnings of each exosomopathy
mutation in an in vivo system. To achieve this goal, I will 1) examine RNA exosome complex integrity comparing
the two exosomopathy mutant models (Aim 1); 2) assess differentially affected RNA exosome interactions in
exosomopathy mutant models using both targeted biochemical assays and discovery-based genetic screens
(Aim 2); and 3) employ RNA-Seq to define the spectrum of RNAs altered by exosomopathy-modeled amino acid
substitutions (Aim 3). This proposed comparative study...

## Key facts

- **NIH application ID:** 9992485
- **Project number:** 1F31GM134649-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Maria Carson Sterrett
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992485

## Citation

> US National Institutes of Health, RePORTER application 9992485, A Budding Yeast Model for Human Disease-Mutations in the RNA Exosome (1F31GM134649-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9992485. Licensed CC0.

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