Q9NSU2 · TREX1_HUMAN
- ProteinThree-prime repair exonuclease 1
- GeneTREX1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids314 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Prevents cell-intrinsic initiation of autoimmunity (PubMed:10391904, PubMed:10393201, PubMed:17293595).
Acts by metabolizing DNA fragments from endogenous retroelements, including L1, LTR and SINE elements (PubMed:10391904, PubMed:10393201, PubMed:17293595).
Plays a key role in degradation of DNA fragments at cytosolic micronuclei arising from genome instability: its association with the endoplasmic reticulum membrane directs TREX1 to ruptured micronuclei, leading to micronuclear DNA degradation (PubMed:33476576).
Micronuclear DNA degradation is required to limit CGAS activation and subsequent inflammation (PubMed:33476576).
Unless degraded, these DNA fragments accumulate in the cytosol and activate the cGAS-STING innate immune signaling, leading to the production of type I interferon (PubMed:33476576).
Prevents chronic ATM-dependent checkpoint activation, by processing ssDNA polynucleotide species arising from the processing of aberrant DNA replication intermediates (PubMed:18045533).
Inefficiently degrades oxidized DNA, such as that generated upon antimicrobial reactive oxygen production or upon absorption of UV light (PubMed:23993650).
During GZMA-mediated cell death, contributes to DNA damage in concert with NME1 (PubMed:16818237).
NME1 nicks one strand of DNA and TREX1 removes bases from the free 3' end to enhance DNA damage and prevent DNA end reannealing and rapid repair (PubMed:16818237).
Catalytic activity
Cofactor
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 18 | Mg2+ 1 (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 18 | Mg2+ 2 (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 20 | Mg2+ 1 (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 20-21 | substrate | ||||
Sequence: EA | ||||||
Binding site | 129 | substrate | ||||
Sequence: Y | ||||||
Active site | 195 | Proton donor/acceptor | ||||
Sequence: H | ||||||
Binding site | 200 | Mg2+ 1 (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 200 | substrate | ||||
Sequence: D |
GO annotations
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameThree-prime repair exonuclease 1
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9NSU2
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Localization to the endoplasmic reticulum membrane is required to direct TREX1 to ruptured micronuclei (PubMed:33476576).
In response to DNA damage, translocates to the nucleus where it is specifically recruited to replication foci (PubMed:16818237).
Translocation to the nucleus also occurs during GZMA-mediated cell death (PubMed:16818237).
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Aicardi-Goutieres syndrome 1 (AGS1)
- Note
- DescriptionA form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.
- See alsoMIM:225750
Natural variants in AGS1
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_037948 | 18 | D>N | in CHBL1 and AGS1; autosomal dominant form; loss of 3'-to-5' DNA exonuclease activity; abolished ability to degrade micronuclear DNA and restrict activation of innate immune response; dbSNP:rs121908117 | |
VAR_028319 | 114 | R>H | in AGS1 and SLE; primary fibroblasts from an AGS1 patient carrying H-169 show defective G1/S transition and chronic G2/MDNA damage checkpoint activation; strongly reduces activity; dbSNP:rs72556554 | |
VAR_070899 | 122 | V>A | in AGS1; increases ubiquitination levels; no effect on exonuclease activity; dbSNP:rs79993407 | |
VAR_070900 | 198 | E>K | in AGS1; increases ubiquitination levels; no effect on exonuclease activity; dbSNP:rs1416519719 | |
VAR_028320 | 200 | D>DD | in AGS1; heterozygous compound with H-169; loss of activity | |
VAR_070901 | 200 | D>H | in AGS1 and SLE | |
VAR_032940 | 200 | D>N | in AGS1; autosomal dominant form; no effect on dsDNA exonuclease activity; abolishes ssDNA exonuclease activity; dbSNP:rs78846775 | |
VAR_028321 | 201 | V>D | in AGS1; reduces activity by 75%; dbSNP:rs78408272 | |
VAR_070902 | 303 | T>P | in AGS1; decreases ubiquitination levels; decreases colocalization with UBQLN1; no effect on exonuclease activity; dbSNP:rs76224909 |
Systemic lupus erythematosus (SLE)
- Note
- DescriptionA chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow.
- See alsoMIM:152700
Natural variants in SLE
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_028319 | 114 | R>H | in AGS1 and SLE; primary fibroblasts from an AGS1 patient carrying H-169 show defective G1/S transition and chronic G2/MDNA damage checkpoint activation; strongly reduces activity; dbSNP:rs72556554 | |
VAR_037949 | 158 | A>V | in SLE; dbSNP:rs762011967 | |
VAR_070901 | 200 | D>H | in AGS1 and SLE | |
VAR_037950 | 227 | G>S | in SLE; associated in cis with P-302; dbSNP:rs113107733 | |
VAR_037951 | 240 | R>S | in SLE; dbSNP:rs72556555 | |
VAR_037952 | 247 | A>P | in SLE; associated in cis with S-282; dbSNP:rs112741962 | |
VAR_037954 | 290 | P>L | in SLE; increases ubiquitination levels; no effect on exonuclease activity; dbSNP:rs148833270 | |
VAR_037955 | 305 | Y>C | in SLE; decreases ubiquitination levels; decreases colocalization with UBQLN1; no effect on exonuclease activity; dbSNP:rs370504038 | |
VAR_037956 | 306 | G>A | in SLE; dbSNP:rs780022923 |
Chilblain lupus 1 (CHBL1)
- Note
- DescriptionA rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure.
- See alsoMIM:610448
Natural variants in CHBL1
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_037948 | 18 | D>N | in CHBL1 and AGS1; autosomal dominant form; loss of 3'-to-5' DNA exonuclease activity; abolished ability to degrade micronuclear DNA and restrict activation of innate immune response; dbSNP:rs121908117 |
Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations (RVCLS)
- Note
- DescriptionAn adult-onset, autosomal dominant endotheliopathy affecting the microvessels of the brain. It results in central nervous system degeneration and retinopathy, with progressive loss of vision, stroke, motor impairment, and cognitive decline. The ocular manifestations are characterized by telangiectasias, microaneurysms and retinal capillary obliteration starting in the macula. Diseased cerebral white matter has prominent small infarcts that often coalesce to pseudotumors. A subset of patients have systemic vascular involvement that can manifest as Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction.
- See alsoMIM:192315
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_037948 | 18 | in CHBL1 and AGS1; autosomal dominant form; loss of 3'-to-5' DNA exonuclease activity; abolished ability to degrade micronuclear DNA and restrict activation of innate immune response; dbSNP:rs121908117 | |||
Sequence: D → N | ||||||
Mutagenesis | 30 | Reduces ubiquitination. | ||||
Sequence: K → R | ||||||
Mutagenesis | 66 | No effect on ubiquitination. | ||||
Sequence: K → R | ||||||
Mutagenesis | 75 | Reduces ubiquitination. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_028319 | 114 | in AGS1 and SLE; primary fibroblasts from an AGS1 patient carrying H-169 show defective G1/S transition and chronic G2/MDNA damage checkpoint activation; strongly reduces activity; dbSNP:rs72556554 | |||
Sequence: R → H | ||||||
Natural variant | VAR_070899 | 122 | in AGS1; increases ubiquitination levels; no effect on exonuclease activity; dbSNP:rs79993407 | |||
Sequence: V → A | ||||||
Natural variant | VAR_037949 | 158 | in SLE; dbSNP:rs762011967 | |||
Sequence: A → V | ||||||
Mutagenesis | 160 | Reduces ubiquitination. | ||||
Sequence: K → R | ||||||
Mutagenesis | 175 | Reduces ubiquitination. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_070900 | 198 | in AGS1; increases ubiquitination levels; no effect on exonuclease activity; dbSNP:rs1416519719 | |||
Sequence: E → K | ||||||
Natural variant | VAR_028320 | 200 | in AGS1; heterozygous compound with H-169; loss of activity | |||
Sequence: D → DD | ||||||
Natural variant | VAR_070901 | 200 | in AGS1 and SLE | |||
Sequence: D → H | ||||||
Natural variant | VAR_032940 | 200 | in AGS1; autosomal dominant form; no effect on dsDNA exonuclease activity; abolishes ssDNA exonuclease activity; dbSNP:rs78846775 | |||
Sequence: D → N | ||||||
Natural variant | VAR_028321 | 201 | in AGS1; reduces activity by 75%; dbSNP:rs78408272 | |||
Sequence: V → D | ||||||
Natural variant | VAR_037950 | 227 | in SLE; associated in cis with P-302; dbSNP:rs113107733 | |||
Sequence: G → S | ||||||
Natural variant | VAR_037951 | 240 | in SLE; dbSNP:rs72556555 | |||
Sequence: R → S | ||||||
Mutagenesis | 242 | Reduces ubiquitination. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_037952 | 247 | in SLE; associated in cis with S-282; dbSNP:rs112741962 | |||
Sequence: A → P | ||||||
Natural variant | VAR_037953 | 266 | in dbSNP:rs55999987 | |||
Sequence: E → G | ||||||
Mutagenesis | 271 | Reduces ubiquitination. Strongly reduces ubiquitination; when associated with R-277. | ||||
Sequence: K → R | ||||||
Mutagenesis | 277 | Reduces ubiquitination. Strongly reduces ubiquitination; when associated with R-271. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_037954 | 290 | in SLE; increases ubiquitination levels; no effect on exonuclease activity; dbSNP:rs148833270 | |||
Sequence: P → L | ||||||
Natural variant | VAR_070902 | 303 | in AGS1; decreases ubiquitination levels; decreases colocalization with UBQLN1; no effect on exonuclease activity; dbSNP:rs76224909 | |||
Sequence: T → P | ||||||
Natural variant | VAR_037955 | 305 | in SLE; decreases ubiquitination levels; decreases colocalization with UBQLN1; no effect on exonuclease activity; dbSNP:rs370504038 | |||
Sequence: Y → C | ||||||
Natural variant | VAR_037956 | 306 | in SLE; dbSNP:rs780022923 | |||
Sequence: G → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 521 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000109868 | 1-314 | UniProt | Three-prime repair exonuclease 1 | |||
Sequence: MGSQALPPGPMQTLIFFDMEATGLPFSQPKVTELCLLAVHRCALESPPTSQGPPPTVPPPPRVVDKLSLCVAPGKACSPAASEITGLSTAVLAAHGRQCFDDNLANLLLAFLRRQPQPWCLVAHNGDRYDFPLLQAELAMLGLTSALDGAFCVDSITALKALERASSPSEHGPRKSYSLGSIYTRLYGQSPPDSHTAEGDVLALLSICQWRPQALLRWVDAHARPFGTIRPMYGVTASARTKPRPSAVTTTAHLATTRNTSPSLGESRGTKDLPPVKDPGALSREGLLAPLGLLAILTLAVATLYGLSLATPGE | |||||||
Modified residue | 78 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 166 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 167 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 167 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 261 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 261 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Gene expression databases
Organism-specific databases
Interaction
Subunit
Interacts (via proline-rich region) with TCERG1/CA150 (via the second WW domain) (By similarity).
Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1 (PubMed:16818237).
Within this complex, directly interacts with SET; this interaction does not result in TREX1 inhibition (PubMed:16818237).
Also interacts with NME1, but only following translocation to the nucleus (PubMed:16818237).
Directly interacts with UBQLN1 (via ubiquitin-like domain); the interaction may control TREX1 subcellular location (PubMed:23979357).
Binary interactions
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 236-314 | Necessary for endoplasmic reticulum localization | ||||
Sequence: TASARTKPRPSAVTTTAHLATTRNTSPSLGESRGTKDLPPVKDPGALSREGLLAPLGLLAILTLAVATLYGLSLATPGE | ||||||
Region | 240-278 | Disordered | ||||
Sequence: RTKPRPSAVTTTAHLATTRNTSPSLGESRGTKDLPPVKD | ||||||
Compositional bias | 242-267 | Polar residues | ||||
Sequence: KPRPSAVTTTAHLATTRNTSPSLGES | ||||||
Region | 243-314 | Interaction with UBQLN1 | ||||
Sequence: PRPSAVTTTAHLATTRNTSPSLGESRGTKDLPPVKDPGALSREGLLAPLGLLAILTLAVATLYGLSLATPGE | ||||||
Region | 281-314 | Necessary for cytoplasmic retention | ||||
Sequence: ALSREGLLAPLGLLAILTLAVATLYGLSLATPGE |
Sequence similarities
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 3 isoforms produced by Alternative splicing.
Q9NSU2-3
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name3
- Length314
- Mass (Da)33,212
- Last updated2017-12-20 v2
- ChecksumEE8F63B6496D72F4
Q9NSU2-1
- Name1
- Differences from canonical
- 1-1: M → MGPGARRQGRIVQGRPEMCFCPPPTPLPPLRILTLGTHTPTPCSSPGSAAGTYPTM
Q9NSU2-2
- Name2
- Differences from canonical
- 1-10: Missing
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
C9J052 | C9J052_HUMAN | TREX1 | 175 |
Sequence caution
Features
Showing features for alternative sequence, compositional bias, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_059279 | 1 | in isoform 1 | |||
Sequence: M → MGPGARRQGRIVQGRPEMCFCPPPTPLPPLRILTLGTHTPTPCSSPGSAAGTYPTM | ||||||
Alternative sequence | VSP_010445 | 1-10 | in isoform 2 | |||
Sequence: Missing | ||||||
Compositional bias | 242-267 | Polar residues | ||||
Sequence: KPRPSAVTTTAHLATTRNTSPSLGES | ||||||
Sequence conflict | 265 | in Ref. 1; CAB50866 | ||||
Sequence: G → R |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AJ243797 EMBL· GenBank· DDBJ | CAB50866.1 EMBL· GenBank· DDBJ | mRNA | ||
AF151105 EMBL· GenBank· DDBJ | AAD48774.2 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AF319566 EMBL· GenBank· DDBJ | AAK07613.1 EMBL· GenBank· DDBJ | mRNA | ||
AF319567 EMBL· GenBank· DDBJ | AAK07614.1 EMBL· GenBank· DDBJ | mRNA | ||
AF319568 EMBL· GenBank· DDBJ | AAK07615.1 EMBL· GenBank· DDBJ | mRNA | ||
AF319569 EMBL· GenBank· DDBJ | AAK07616.1 EMBL· GenBank· DDBJ | mRNA | ||
AK315196 EMBL· GenBank· DDBJ | BAG37636.1 EMBL· GenBank· DDBJ | mRNA | ||
AL137745 EMBL· GenBank· DDBJ | - | mRNA | No translation available. | |
AF483777 EMBL· GenBank· DDBJ | AAL82504.1 EMBL· GenBank· DDBJ | Genomic DNA | Different initiation | |
BC023630 EMBL· GenBank· DDBJ | AAH23630.1 EMBL· GenBank· DDBJ | mRNA |