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Updated: Dec 24, 2025
Mating-based Overexpression Library Screening in Yeast
Published on: July 6, 2018
A Genetic Screen for Human Genes Suppressing FUS Induced Toxicity in Yeast
Elliott Hayden1, Shuzhen Chen1, Abagail Chumley1
1Department of Biological Sciences, Wright State University, Dayton, OH 45435 and.
Abstract:
FUS is a nucleic acid binding protein that, when mutated, cause a subset of familial amyotrophic lateral sclerosis (ALS). Expression of FUS in yeast recapitulates several pathological features of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, formation of cytoplasmic inclusions, and cytotoxicity. Genetic screens using the yeast model of FUS have identified yeast genes and their corresponding human homologs suppressing FUS induced toxicity in yeast, neurons and animal models. To expand the search for human suppressor genes of FUS induced toxicity, we carried out a genome-scale genetic screen using a newly constructed library containing 13570 human genes cloned in an inducible yeast-expression vector. Through multiple rounds of verification, we found 37 human genes that, when overexpressed, suppress FUS induced toxicity in yeast. Human genes with DNA or RNA binding functions are overrepresented among the identified suppressor genes, supporting that perturbations of RNA metabolism is a key underlying mechanism of FUS toxicity.
Insights
Researchers identified 37 human genes that suppress toxicity caused by mutated FUS protein, a key factor in familial amyotrophic lateral sclerosis (ALS). These findings highlight the role of RNA metabolism in FUS-related neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Mutations in the FUS gene are linked to familial amyotrophic lateral sclerosis (ALS).
- FUS protein toxicity in yeast models mimics key pathological features observed in ALS patients.
- Previous studies utilized yeast genetic screens to identify suppressors of FUS-induced toxicity.
Purpose of the Study:
- To identify novel human genes that can suppress FUS-induced toxicity.
- To expand the understanding of the molecular mechanisms underlying FUS toxicity and ALS pathogenesis.
Main Methods:
- A genome-scale genetic screen was performed in yeast using a library of 13,570 human genes.
- Overexpression of human genes was tested for their ability to suppress FUS-induced cytotoxicity in yeast.
- Identified suppressor genes were verified through multiple rounds of testing.
Main Results:
- 37 human genes were identified that suppress FUS-induced toxicity when overexpressed in yeast.
- Genes involved in DNA or RNA binding functions were significantly overrepresented among the identified suppressors.
- This suggests that disruptions in RNA metabolism are central to FUS toxicity.
Conclusions:
- The study identified novel human suppressor genes for FUS toxicity, offering potential therapeutic targets for ALS.
- The findings reinforce the critical role of RNA metabolism perturbations in the pathogenesis of FUS-related neurodegenerative diseases.
- The yeast model proves effective for discovering conserved genetic suppressors of human disease genes.
