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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
Author(s) -
Sariki Santhosh Kumar,
Sahu Pushpendra Kumar,
Golla Upendarrao,
Singh Vikash,
Azad Gajendra Kumar,
Tomar Raghuvir S.
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13917
Subject(s) - biology , saccharomyces cerevisiae , mutant , microbiology and biotechnology , mitochondrion , dna damage , unfolded protein response , mutation , programmed cell death , biochemistry , gene , dna , apoptosis
Mutations in the Senataxin gene, SETX are known to cause the neurodegenerative disorders, ataxia with oculomotor apraxia type 2 ( AOA 2), and amyotrophic lateral sclerosis 4 ( ALS 4). 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.