Three prime repair exonuclease 1 is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''TREX1''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Function
This gene encodes the major 3'->5' DNA
exonuclease
Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is th ...
in human cells. The protein is a non-processive exonuclease that may serve a proofreading function for a human DNA polymerase. It is also a component of the SET complex, and acts to rapidly degrade 3' ends of nicked DNA during granzyme A-mediated cell death. Mutations in this gene result in
Aicardi-Goutieres syndrome, chilblain lupus,
RVCL (Retinal Vasculopathy with Cerebral Leukodystrophy), and Cree encephalitis. Multiple transcript variants encoding different isoforms have been found for this gene.
Clinical relevance
Mutations within the ''TREX1'' gene cause familial
chilblain lupus. The ''TREX1'' polymorphisms confer susceptibility to
systemic lupus erythematosus
Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
. Missense mutations of the ''TREX1'' gene significantly downregulate its exonucleolytic capacity and result in the accumulation of nucleic acids. The build-up of the nucleic acids within the cytoplasm stimulates type-I
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...
responses that could trigger autoimmune responses.
The region containing the ''TREX1'' gene (3p21.31) has been linked to
COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic.
The symptoms of COVID‑19 can vary but often include fever ...
severity in a recent genome-wide association study. This might explain the occurrence of chilblain like lesions in patients infected with SARS-CoV-2.
[
TREX1 helps HIV‑1 to evade cytosolic sensing by degrading viral cDNA in the cytoplasm]Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in TREX1 can give cause failure to appropriately remove ribonucleotide
In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic mo ...
s misincorporated into DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
.nucleotide excision repair
Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. Intercalation (biochemistry), intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single ...
. In humans, a defect in this process can give rise to Aicardi-Goutieres syndrome involving microcephaly
Microcephaly (from Neo-Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it m ...
and neuroinflammation
Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...
.[
]
Homology directed DNA repair
TREX1 is the most abundant 3’-5’ DNA exonuclease
Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is th ...
in mammals.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. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is constantly modified ...
and premature senescence
Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...
phenotypes in humans, mice and ''Drosophila
''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
''.[ Such TREX1 variants can also cause adult onset small vessel disease known as vasculopathy with cerebral ]leukoencephalopathy
Leukoencephalopathy ( leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. It can refer specifically to any of these diseases:
* Progressive multifocal le ...
.[
]
References
Further reading
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External links
OMIM entries on Aicardi-Goutieres syndrome
{{Esterases