E3 ubiquitin-protein ligase RAD18 is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that in humans is encoded by the ''RAD18''
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 b ...
.
Function
The protein encoded by this gene is highly similar to
S. cerevisiae DNA damage repair protein Rad18. Yeast Rad18 functions through interaction with Rad6, which is a ubiquitin-conjugating enzyme required for post-replication repair of damaged DNA. Similar to its yeast counterpart, this protein is able to interact with the human homolog of yeast Rad6 protein through a conserved ring finger motif. Mutation of this motif results in defective replication of UV-damaged DNA and hypersensitivity to multiple mutagens.
Animal models
Model organisms have been used in the study of ''RAD18'' function. A
conditional
Conditional (if then) may refer to:
* Causal conditional, if X then Y, where X is a cause of Y
* Conditional probability, the probability of an event A given that another event B has occurred
*Conditional proof, in logic: a proof that asserts a ...
knockout mouse
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importa ...
line, called ''Rad18
tm1a(EUCOMM)Wtsi'', was generated as part of the
EUCOMM The European Conditional Mouse Mutagenesis Program or EUCOMM is an EU-funded program to generate a library of mutant mouse embryonic stem cells for research purposes.
Setup
The EUCOMM program is funded by the European Union sixth R&D program ...
program — a high-throughput
mutagenesis
Mutagenesis () is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using l ...
project to generate and distribute animal models of disease to interested scientists — at the
Wellcome Trust Sanger Institute
The Wellcome Sanger Institute, previously known as The Sanger Centre and Wellcome Trust Sanger Institute, is a non-profit British genomics and genetics research institute, primarily funded by the Wellcome Trust.
It is located on the Wellcome Ge ...
.
Mice lacking ''Rad18'' had no significant defects in viability or
fertility
Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Ferti ...
, therefore male and female animals underwent a standardized
phenotypic screen
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...
to determine the effects of deletion.
Twenty five tests were carried out and four significant
phenotypes
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...
were reported:
[
* ]Mutant
In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
male mice had a decreased body weight
Human body weight is a person's Mass versus weight, mass or weight.
Strictly speaking, body weight is the measurement of weight without items located on the person. Practically though, body weight may be measured with clothes on, but without shoe ...
compared to wildtype
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
control mice.
* Mutant male mice showed increased activity, VO2 and energy expenditure In biology, energy homeostasis, or the homeostatic control of energy balance, is a biological process that involves the coordinated homeostatic regulation of food intake (energy inflow) and energy expenditure (energy outflow). The human brain, par ...
, determined by indirect calorimetry
Indirect calorimetry calculates heat that living organisms produce by measuring either their production of carbon dioxide and nitrogen waste (frequently ammonia in aquatic organisms, or urea in terrestrial ones), or from their consumption of oxyg ...
.
* Dual-energy X-ray absorptiometry
Dual-energy X-ray absorptiometry (DXA, or DEXA) is a means of measuring bone mineral density (BMD) using spectral imaging. Two X-ray beams, with different energy levels, are aimed at the patient's bones. When soft tissue absorption is subtracte ...
(DEXA) showed mutant male mice had a decrease in fat
In nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such compounds, most commonly those that occur in living beings or in food.
The term often refers specifically to triglycerides (triple es ...
mass.
* A micronucleus test
A micronucleus test is a test used in toxicological screening for potential genotoxic compounds. The assay is now recognized as one of the most successful and reliable assays for genotoxic carcinogens, i.e., carcinogens that act by causing genetic ...
found a potential increase in DNA damage
DNA repair is 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 radiation can cause DNA da ...
in mutant mice.
A knockout in a human colorectal cancer cell line, HCT116, has also been created.
Interactions
RAD18 has been shown to interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizat ...
with HLTF,[
]
References
Further reading
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{{refend
Genes mutated in mice
DNA repair