Stress-induced upregulation of the ubiquitin-relative Hub1 modulates pre-mRNA splicing and facilitates cadmium tolerance in Saccharomyces cerevisiae

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Highlights

  • The ubiquitin relative Hub1 is upregulated upon stresses by Yap1 regulon.

  • Hub1 is required for survival upon cadmium stress when metallothionein is absent.

  • Hub1 promotes non-canonical splicing under cadmium exposure.

Abstract

Splicing is a fundamental RNA-processing step for eukaryotic gene expression involved in the removal of intronic sequences of pre-mRNA. As the process is utilized for quantitative and qualitative regulation of gene expression, uncontrolled splicing can result in potential cellular dysfunctions. Accumulating evidence suggests that fidelity of splicing is regulated by a family of DEAD/DExH-box RNA helicases. Recently, we have shown that the evolutionarily-conserved ubiquitin-relative Hub1 binds directly to the DEAD-box RNA helicase Prp5, a key regulator of splicing fidelity, and stimulates its ATPase activity. When overexpressed, Hub1 enhances splicing efficiency and relaxes the constraints on splice-site and branch-site usages; yet physiological relevance of cellular Hub1 overexpression remains unknown. Here we show that Hub1 is upregulated at the transcriptional level via the yeast-specific AP1 regulon upon oxidative and heavy metal stresses, and promotes efficient splicing of introns with non-canonical splice-sites. While nonessential for yeast viability, Hub1 becomes important for cadmium tolerance when metallothionein-mediated defense system is impaired. Moreover, mutant variants of other splicing factors also showed a similar cadmium sensitivity, suggesting the role of splicing in facilitating tolerance of heavy metal stress. Taken together, we propose that cells adjust gene expression landscape required for heavy metal detoxification by promoting intron-specific splicing through the stress-induced overexpression of Hub1.

Keywords

Ubiquitin-like protein
Stress response
Cadmium
Splicing
Homologous to ubiquitin 1

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