Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly

Bennett, Craig L., Sopher, Bryce L. and La Spada, Albert R. (2020) Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly. Heliyon, 6 (6). e04165. ISSN 2405-8440

Full content URL: https://doi.org/10.1016/j.heliyon.2020.e04165

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Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly
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Abstract

The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and recessive SETX mutations cause a severe ataxia, known as Ataxia with Oculomotor Apraxia type 2, while dominant SETX mutations cause Amyotrophic Lateral Sclerosis type 4. SETX is a very low abundance protein, and its expression is tightly regulated, such that large increases in mRNA levels fail to significantly increase protein levels. Despite this, transient transfection in cell culture can boost SETX protein levels on an individual cell basis. Here we found that over-expression of normal SETX, but not enzymatically-dead SETX, is associated with S-phase cell-cycle arrest in HEK293A cells. As SETX interacts with the nuclear exosome to ensure degradation of incomplete RNA transcripts, and SETX localizes to sites of collision between the DNA replication machinery and the RNAP II complex, altered dosage or aberrant function of SETX may impede this process to promote S-phase cell-cycle arrest. Because neurons are enriched for long transcripts with additional antisense regulatory transcription, collisions of RNAP II complexes may occur in such post-mitotic cells, underscoring a role for SETX in maintaining neuron homeostasis.

Keywords:Cell biology, Genetics, Neuroscience, Infectious disease, Gene expression, Gene regulation, Mutation, Senataxin, Helicase, Fibrillarin, ALS4, Nucleolus, Ataxia
Subjects:C Biological Sciences > C130 Cell Biology
C Biological Sciences > C431 Medical Genetics
Divisions:College of Science > School of Life Sciences
ID Code:42818
Deposited On:28 Oct 2020 09:36

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