Three prime repair exonuclease 1 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 ''TREX1''
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 ...
.
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 the ...
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
Chilblains, also known as pernio, is a medical condition in which damage occurs to capillary beds in the skin, most often in the hands or feet, when blood perfuses into the nearby tissue resulting in redness, itching, inflammation, and possibly ...
lupus. The ''TREX1'' polymorphisms confer susceptibility to
systemic lupus erythematosus
Lupus, technically known as 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. Comm ...
. 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 the ...
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 a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
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, mi ...
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 m ...
s misincorporated into
DNA.
[McKinnon PJ. Genome integrity and disease prevention in the nervous system. Genes Dev. 2017 Jun 15;31(12):1180-1194. doi: 10.1101/gad.301325.117. PMID: 28765160; PMCID: PMC5558921] The removal process is ordinary performed by ribo
nucleotide excision repair
Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucle ...
. In humans, a defect in this process can give rise to
Aicardi-Goutieres syndrome involving
microcephaly
Microcephaly (from New 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 ...
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 ...
.
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References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Aicardi-Goutières Syndrome
OMIM entries on Aicardi-Goutieres syndrome
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