title: 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.
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.
authors.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: Santhosh Kumar
authors.initials: SK
authors.lastname: Sariki
authors.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: Pushpendra Kumar
authors.initials: PK
authors.lastname: Sahu
authors.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: Upendarrao
authors.initials: U
authors.lastname: Golla
authors.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: Vikash
authors.initials: V
authors.lastname: Singh
authors.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: Gajendra Kumar
authors.initials: GK
authors.lastname: Azad
authors.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: Raghuvir S
authors.initials: RS
authors.lastname: Tomar
mesh_terms: D001343:Autophagy / Q000235:genetics; D002308:Cardiolipins / Q000096:biosynthesis; D016922:Cellular Senescence / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D050296:Microbial Viability / Q000235:genetics; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D064251:Multifunctional Enzymes; D009154:Mutation; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D020365:RNA Helicases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D002308:Cardiolipins; D064251:Multifunctional Enzymes; D029701:Saccharomyces cerevisiae Proteins; D017346:Protein Serine-Threonine Kinases; C500749:target of rapamycin protein, S cerevisiae; C542347:SEN1 protein, S cerevisiae; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases
keywords: apoptosis; chronological aging; reactive oxygen species; senataxin; unfolded protein response