Probable helicase senataxin is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''SETX''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
This gene encodes a protein named senataxin, a 302kDa protein
Sequence and structure
There is high homology between human SETX and yeast Sen1. Sen1 in yeast is a RNA/DNA
helicase
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separatin ...
and the highly conserved sequences between these genes, particularly in the helicase domain, indicates that SETX in humans may have similar roles in
gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
and maintaining
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
stability. In Sen1, the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
has shown interactions with the
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
domain of
RNA polymerase II
RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryoti ...
,
ribonuclease III
Ribonuclease III (RNase III or RNase C)(BREND3.1.26.3 is a type of ribonuclease that recognizes RNA, dsRNA and cleaves it at specific targeted locations to transform them into mature RNAs. These enzymes are a group of endoribonucleases that are c ...
, and NER factor
Rad2/XPG. Meanwhile, the C-terminus encodes the DNA/RNA helicase activity. Similarly, SETX encodes the senataxin protein that has a N-terminal that is likely to be involved with interacting with other proteins. Senataxin interacts with RNA polymerase II and poly(A) binding proteins. At the C-terminal, senataxin has a
DEAD box
Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
helicase domain.
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
R-loop
An R-loop is a three-stranded nucleic acid structure, composed of a DNA:RNA hybrid and the associated non-template single-stranded DNA. R-loops may be formed in a variety of circumstances, and may be tolerated or cleared by cellular components. T ...
s,
transcription termination, and maintaining genome stability by being an essential component of the
DNA-damage response
DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolism, metabolic activities and environmental factors such as r ...
(DDR).
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. At these collision sites, SETX was shown to co-localize with 53BP1, which is a marker for DNA damage. Furthermore, SETX was observed to promote homologous recombination repair and prevent translocation. 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. 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.
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.
Clinical significance
SETX was found to be mutated in juvenile ataxia with oculomotor apraxia type 2 (AOA2) and juvenile form of
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS4). In ALS4 cells, SETX are mutated to have more helicase function, resulting in lower R-loop levels then usual, which causes abnormal TGF-β signaling and causes neuron death. AOA2 cells show senataxin loss of function and abnormally high R-loop levels. Neurological diseases such AOA2 and ALS4 are frequently shown to have abnormal accumulation of protein aggregates and research shows that SETX may have an essential role in autophagy by regulating genes involved in clearing protein aggregates.
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Ataxia with Oculomotor Apraxia Type 2 OMIM entries on Ataxia with Oculomotor Apraxia Type 2Genetics Home Reference
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