SETX
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Location (UCSC) | Chr 9: 132.26 – 132.35 Mb | Chr 2: 29.01 – 29.07 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Probable helicase senataxin is an enzyme that in humans is encoded by the SETX gene.[5][6][7]
This gene encodes a protein named senataxin, a 302kDa protein[8]
Sequence and structure
There is high homology between human SETX and yeast Sen1. Sen1 in yeast is a RNA/DNA
Function
Although senataxin is widely expressed in many tissues in the body, the cellular roles of senataxin are not completely understood. However, based on current research and examining homologs of SETX, senataxin is thought to play an important role in resolving
SETX is suspected to be involved in DNA damage repair and maintaining genome stability by working with other proteins in the DNA damage response. R loops may arise from replication stress, such as when transcription and replication occur at the same time at a certain loci. This often occurs when transcribing long genes since transcription of that gene can take longer than one round of replication. When the replisome and transcription machinery collide, R loops can form and double stranded breaks can form.[12] At these collision sites, SETX was shown to co-localize with 53BP1, which is a marker for DNA damage.[13] Furthermore, SETX was observed to promote homologous recombination repair and prevent translocation.[14] To further support SETX's role in DNA damage repair, SETX co-localizes with many other DDR factors. For example, BRCA1 was also shown to recruit SETX to remove R-loops, which prevents DNA mutations that arise as a result of the vulnerable single stranded DNA that is part of the R-loop structure.[15] SETX may be involved in double strand break repair through its involvement in loading RAD51, which is a crucial protein in double strand break repair through homologous recombination.[16]
Furthermore, Senataxin may be involved in transcription termination. A large amount of R-loops are found at the 3’ end of some mammalian genes, after poly-adenylation sites. The R-loops are thought to be involved in transcription termination by stalling RNA polymerase II. The senataxin protein, which has RNA-DNA helicase activity, and DHX9 human helicase can resolve R-loops. This allows XRN2, an exonuclease, to access the 3’ cleavage polyadenylated sites and degrade the 3’ transcript. This ultimately leads to termination of transcription.[17]
Clinical significance
SETX was found to be mutated in juvenile ataxia with oculomotor apraxia type 2 (AOA2) and juvenile form of
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000107290 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000043535 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9497266.
- PMID 11022012.
- ^ "Entrez Gene: SETX senataxin".
- PMID 27771483.
- PMID 24746923.
- PMID 24990962.
- PMID 23149945.
- PMID 27600412.
- PMID 24746923.
- PMID 29416069.
- PMID 30735654.
- PMID 29416069.
- PMID 21700224.
- PMID 32686621.
- PMID 29395064.
- PMID 30735654.
- PMID 33642381.
Further reading
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. PMID 8125298.
- Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. PMID 8889548.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. PMID 9373149.
- Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, et al. (June 1998). "Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research. 5 (3): 169–76. PMID 9734811.
- Moreira MC, Klur S, Watanabe M, Németh AH, Le Ber I, Moniz JC, et al. (March 2004). "Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2". Nature Genetics. 36 (3): 225–7. PMID 14770181.
- Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, et al. (June 2004). "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)". American Journal of Human Genetics. 74 (6): 1128–35. PMID 15106121.
- Duquette A, Roddier K, McNabb-Baltar J, Gosselin I, St-Denis A, Dicaire MJ, et al. (March 2005). "Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy". Annals of Neurology. 57 (3): 408–14. S2CID 9501982.
- Asaka T, Yokoji H, Ito J, Yamaguchi K, Matsushima A (May 2006). "Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX". Neurology. 66 (10): 1580–1. S2CID 34988349.
- Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (October 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology. 24 (10): 1285–92. S2CID 14294292.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (November 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. S2CID 7827573.
- Suraweera A, Becherel OJ, Chen P, Rundle N, Woods R, Nakamura J, et al. (June 2007). "Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage". The Journal of Cell Biology. 177 (6): 969–79. PMID 17562789.