Slx4
Encyclopedia
SLX4 is a protein
involved in DNA repair
, where it has important roles in the final steps of homologous recombination
. Mutations in the gene are associated with the disease Fanconi anemia
The version of SLX4 present in humans and other mammals acts as a sort of scaffold upon which other proteins form several different multiprotein complexes. The SLX1-SLX4 complex acts as a Holliday junction
resolvase. As such, the complex cleaves the links between two homologous chromosomes that form during homologous recombination. This allows the two linked chromosomes to resolve into two unconnected double-strand DNA molecules. SLX4 also associates with RAD1
, RAD10 and SAW1 in the single-strand annealing pathway of homologous recombination.
Model organism
s have been prominant in the study of SLX4 function. It was identified in 2001 during a screen for lethal mutations in yeast
cells lacking a functional copy of the Sgs1
protein. Based on that, SLX4 was grouped with several other proteins produced by SLX (synthetic lethal of unknown function) genes.
A conditional knockout mouse
line, called Slx4tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium
program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant
mice and ten significant abnormalities were observed. A viability at weaning study found less homozygous mutant
animals were present than predicted by Mendelian ratio. Homozygous mutant animals of both sexes were sub-fertile and homozygous females had a reduced body weight, body length, heart weight, platelet
count and lean mass. Homozygotes of both sex had abnormal eye sizes, narrow eye openings, skeletal defects (including scoliosis
and fusion of vertebrae), and displayed an increase in DNA instability as shown by a micronucleus test
.
This and further analysis revealed the mouse phenotype to model the human genetic illness, Fanconi anemia. The association was confirmed when patients with the disease were found to have mutations in their SLX4 gene.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
involved in DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
, where it has important roles in the final steps of homologous recombination
Homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...
. Mutations in the gene are associated with the disease Fanconi anemia
Fanconi anemia
Fanconi anemia is a genetic disease with an incidence of 1 per 350,000 births, with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa.FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair...
The version of SLX4 present in humans and other mammals acts as a sort of scaffold upon which other proteins form several different multiprotein complexes. The SLX1-SLX4 complex acts as a Holliday junction
Holliday junction
A Holliday junction is a mobile junction between four strands of DNA. The structure is named after Robin Holliday, who proposed it in 1964 to account for a particular type of exchange of genetic information he observed in yeast known as homologous recombination...
resolvase. As such, the complex cleaves the links between two homologous chromosomes that form during homologous recombination. This allows the two linked chromosomes to resolve into two unconnected double-strand DNA molecules. SLX4 also associates with RAD1
RAD1 homolog
Cell cycle checkpoint protein RAD1 is a protein that in humans is encoded by the RAD1 gene.-Interactions:RAD1 homolog has been shown to interact with RAD9A, RAD17 and HUS1.-Further reading:...
, RAD10 and SAW1 in the single-strand annealing pathway of homologous recombination.
Model organisms
Model organism
Model organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
s have been prominant in the study of SLX4 function. It was identified in 2001 during a screen for lethal mutations in yeast
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
cells lacking a functional copy of the Sgs1
Sgs1
Sgs1, also known as small growth suppressor 1, is a DNA helicase protein found in Saccharomyces cerevisiae. It is a homolog of the bacterial RecQ helicase. Like the other members of the RecQ helicase family, Sgs1 is important for DNA repair. In particular, Sgs1 collaborates with other proteins...
protein. Based on that, SLX4 was grouped with several other proteins produced by SLX (synthetic lethal of unknown function) genes.
A conditional knockout mouse
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
line, called Slx4tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium
International Knockout Mouse Consortium
The International Knockout Mouse Consortium is a scientific endeavour to produce a collection of mouse embryonic stem cell lines that together lack every gene in the genome, and then to distribute the cells to scientific researchers to create knockout mice to study...
program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Abnormal |
| Fertility | Abnormal |
| Body weight | Abnormal |
| Anxiety Open Field (animal test) The Open Field Test is an experiment used to assay general locomotor activity levels and anxiety in rodents in scientific research.- Experimental Design :... |
Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate Hot plate test The hot plate test is a test of the pain response in animals. It is used in basic pain research and in testing the effectiveness of analgesics by observing the reaction to pain caused by heat. It was proposed by Eddy and Leimbach in 1953.... |
Normal |
| Dysmorphology | Abnormal |
| Indirect calorimetry | Normal |
| Glucose tolerance test Glucose tolerance test A glucose tolerance test is a medical test in which glucose is given and blood samples taken afterward to determine how quickly it is cleared from the blood. The test is usually used to test for diabetes, insulin resistance, and sometimes reactive hypoglycemia and acromegaly, or rarer disorders of... |
Normal |
| Auditory brainstem response Auditory Brainstem Response The auditory brainstem response is an auditory evoked potential extracted from ongoing electrical activity in the brain and recorded via electrodes placed on the scalp. The resulting recording is a series of vertex positive waves of which I through V are evaluated... |
Normal |
| DEXA | Abnormal |
| Radiography Radiography Radiography is the use of X-rays to view a non-uniformly composed material such as the human body. By using the physical properties of the ray an image can be developed which displays areas of different density and composition.... |
Abnormal |
| Body temperature | Normal |
| Eye morphology | Abnormal |
| Clinical chemistry | Normal |
| Haematology | Abnormal |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test Micronucleus test A micronucleus test is a test used in toxicological screening for potential genotoxic compounds. There are two major versions of this test, one in vivo and the other In vitro. The in vivo test normally uses mouse bone marrow or mouse peripheral blood. Micronuclei were first used to quantify... |
Abnormal |
| Heart weight | Abnormal |
| Skin Histopathology | Normal |
| Brain histopathology | Normal |
| Salmonella Salmonella Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction... infection |
Normal |
| Citrobacter Citrobacter Citrobacter is a genus of Gram-negative coliform bacteria in the Enterobacteriaceae family.The species C. amalonaticus, C. koseri, and C. freundii use solely citrate as a carbon source... infection |
Normal |
| All tests and analysis from |
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant
Mutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
mice and ten significant abnormalities were observed. A viability at weaning study found less homozygous mutant
Mutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
animals were present than predicted by Mendelian ratio. Homozygous mutant animals of both sexes were sub-fertile and homozygous females had a reduced body weight, body length, heart weight, platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count and lean mass. Homozygotes of both sex had abnormal eye sizes, narrow eye openings, skeletal defects (including scoliosis
Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
and fusion of vertebrae), and displayed an increase in DNA instability as shown by a micronucleus test
Micronucleus test
A micronucleus test is a test used in toxicological screening for potential genotoxic compounds. There are two major versions of this test, one in vivo and the other In vitro. The in vivo test normally uses mouse bone marrow or mouse peripheral blood. Micronuclei were first used to quantify...
.
This and further analysis revealed the mouse phenotype to model the human genetic illness, Fanconi anemia. The association was confirmed when patients with the disease were found to have mutations in their SLX4 gene.