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PMID:27718307

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Citation

Sariki, SK, Sahu, PK, Golla, U, Singh, V, Azad, GK and Tomar, RS (2016) Sen1, the homolog of human Senataxin, is critical for cell survival through regulation of redox homeostasis, mitochondrial function, and the TOR pathway in Saccharomyces cerevisiae. FEBS J. 283:4056-4083

Abstract

Mutations in the Senataxin gene, SETX are known to cause the neurodegenerative disorders, ataxia with oculomotor apraxia type 2 (AOA2), and amyotrophic lateral sclerosis 4 (ALS4). However, the mechanism underlying disease pathogenesis is still unclear. The Senataxin N-terminal protein-interaction and C-terminal RNA/DNA helicase domains are conserved in the Saccharomyces cerevisiae homolog, Sen1p. Using genome-wide expression analysis, we first show alterations in key cellular pathways such as: redox, unfolded protein response, and TOR in the yeast sen1 ΔN mutant (N-terminal truncation). This mutant exhibited growth defects on nonfermentable carbon sources, was sensitive to oxidative stress, and showed severe loss of mitochondrial DNA. The growth defect could be partially rescued upon supplementation with reducing agents and antioxidants. Furthermore, the mutant showed higher levels of reactive oxygen species, lower UPR activity, and alterations in mitochondrial membrane potential, increase in vacuole acidity, free calcium ions in the cytosol, and resistance to rapamycin treatment. Notably, the sen1 ∆N mutant showed increased cell death and shortened chronological life span. Given the strong similarity of the yeast and human Sen1 proteins, our study thus provides a mechanism for the progressive neurological disorders associated with mutations in human senataxin.

Links

PubMed Online version:10.1111/febs.13917

Keywords

Autophagy/genetics; Cardiolipins/biosynthesis; Cellular Senescence/genetics; DNA Helicases/genetics; DNA Helicases/metabolism; Gene Expression Profiling/methods; Gene Expression Regulation, Fungal; Gene Regulatory Networks; Homeostasis/genetics; Humans; Immunoblotting; Membrane Potential, Mitochondrial/genetics; Microbial Viability/genetics; Microscopy, Fluorescence; Mitochondria/genetics; Mitochondria/metabolism; Models, Genetic; Mutation; Oxidation-Reduction; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; RNA Helicases/genetics; RNA Helicases/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/growth & development; Saccharomyces cerevisiae/metabolism; Saccharomyces cerevisiae Proteins/genetics; Saccharomyces cerevisiae Proteins/metabolism; Signal Transduction/genetics; Unfolded Protein Response/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

YEAST:SEN1

involved_in

GO:0045454: cell redox homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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