SETX
Domain
The N-terminus domain is necessary for S/G2 nuclear foci localization (PubMed:23149945).
Function
Probable RNA/DNA helicase involved in diverse aspects of RNA metabolism and genomic integrity. Plays a role in transcription regulation by its ability to modulate RNA Polymerase II (Pol II) binding to chromatin and through its interaction with proteins involved in transcription (PubMed:19515850, PubMed:21700224). Contributes to the mRNA splicing efficiency and splice site selection (PubMed:19515850). Required for the resolution of R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site, allowing XRN2 recruitment and XRN2-mediated degradation of the downstream cleaved RNA and hence efficient RNA polymerase II (RNAp II) transcription termination (PubMed:19515850, PubMed:21700224, PubMed:26700805). Required for the 3' transcriptional termination of PER1 and CRY2, thus playing an important role in the circadian rhythm regulation (By similarity). Involved in DNA double-strand breaks damage response generated by oxidative stress (PubMed:17562789). In association with RRP45, targets the RNA exosome complex to sites of transcription-induced DNA damage (PubMed:24105744). Plays a role in the development and maturation of germ cells: essential for male meiosis, acting at the interface of transcription and meiotic recombination, and in the process of gene silencing during meiotic sex chromosome inactivation (MSCI) (By similarity). May be involved in telomeric stability through the regulation of telomere repeat-containing RNA (TERRA) transcription (PubMed:21112256). Plays a role in neurite outgrowth in hippocampal cells through FGF8-activated signaling pathways. Inhibits retinoic acid-induced apoptosis (PubMed:21576111).
Involvement in disease
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
SCAN2
A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAN2 is an autosomal recessive form associated with peripheral neuropathy and elevated serum alpha-fetoprotein, immunoglobulins and, less commonly, creatine kinase levels. Some SCAN2 patients manifest oculomotor apraxia.
None
The disease is caused by variants affecting the gene represented in this entry.
Amyotrophic lateral sclerosis 4
ALS4
A form of amyotrophic lateral sclerosis with childhood- or adolescent-onset, and characterized by slow disease progression and the sparing of bulbar and respiratory muscles. Amyotrophic lateral sclerosis is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Ubiquitinated.
Sumoylated preferentially with SUMO2 or SUMO3 (PubMed:24105744, PubMed:24244371).
Sequence Similarities
Belongs to the DNA2/NAM7 helicase family.
Tissue Specificity
Highly expressed in skeletal muscle. Expressed in heart, fibroblast, placenta and liver. Weakly expressed in brain and lung. Expressed in the cortex of the kidney (highly expressed in tubular epithelial cells but low expression in the glomerulus).
Cellular localization
- Nucleus
- Nucleus
- Nucleoplasm
- Nucleus
- Nucleolus
- Cytoplasm
- Chromosome
- Chromosome
- Telomere
- Cell projection
- Axon
- Cell projection
- Growth cone
- May be detected in the nucleolus only in cycling cells. At pachytene stage, colocalizes predominantly to the heterochromatic XY-body of sex chromosomes with DNA damage response proteins in a BRCA1-dependent manner (By similarity). Localizes with telomeric DNA in a transcription-dependent manner (PubMed:21112256). Under replication stress, colocalizes with a variety of DNA damage signaling and repair response proteins at distinct nuclear foci in mitotic S/G2- and G1-phase cells in a transcription- and RNA/DNA hybrid-dependent manner (PubMed:23149945). Localizes at limited number of nuclear foci (PubMed:24105744). Colocalizes with EXOSC9 in nuclear foci upon induction of transcription-related DNA damage at the S phase (PubMed:24105744). Most abundant in the nucleus. Detected in granules. Colocalized in cycling cells with FBL in the nucleolus.
Alternative names
ALS4, KIAA0625, SCAR1, SETX, Probable helicase senataxin, Amyotrophic lateral sclerosis 4 protein, SEN1 homolog, Senataxin