Major cellular 3'-to-5' DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3' termini (PubMed:10391904, PubMed:11279105, PubMed:15254239, PubMed:17293595, PubMed:17355961, PubMed:18780819). Prevents cell-intrinsic initiation of autoimmunity (PubMed:18724932, PubMed:24218451). Acts by metabolizing DNA fragments from endogenous retroelements, including L1, LTR and SINE elements (PubMed:18724932). 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 (By similarity). Micronuclear DNA degradation is required to limit CGAS activation and subsequent inflammation (By similarity). 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:18724932). 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 (By similarity). 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 (By similarity). Exonucleolytic cleavage in the 3'- to 5'-direction to yield nucleoside 5'-phosphates. Binds 2 Mg(2+) per subunit. The second magnesium ion interacts with only one residue. Substitution with Mn(2+) results in partial activity. Calcium, lithium and sodium inhibit the exonuclease activity but not the DNA binding. Optimum pH is 7.5-8.0. Homodimer (PubMed:17293595, PubMed:17355961, PubMed:22071149). Interacts (via proline-rich region) with TCERG1/CA150 (via the second WW domain) (PubMed:17355961). Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1 (By similarity). Within this complex, directly interacts with SET; this interaction does not result in TREX1 inhibition (By similarity). Also interacts with NME1, but only following translocation to the nucleus (By similarity). Directly interacts with UBQLN1 (via ubiquitin-like domain); the interaction may control TREX1 subcellular location (By similarity). Retained in the cytoplasm through the C-terminal region (PubMed:18045533). Localization to the endoplasmic reticulum membrane is required to direct TREX1 to ruptured micronuclei (By similarity). In response to DNA damage, translocates to the nucleus where it is specifically recruited to replication foci (PubMed:18045533). Translocation to the nucleus also occurs during GZMA-mediated cell death (PubMed:18045533). Widely expressed with high expression levels detected in spleen, thymus and uterus. Induced by cytosolic DNA. Induced by inflammatory stimuli in a cell-specific fashion. Up-regulated by IFN-alpha and IFN-gamma in B-cells and by LPS and viral and bacterial DNA (via Toll-like receptor signaling) in dendritic cells and macrophages. Ubiquitinated, but not targeted to proteasomal degradation. Ubiquitination may be important for interaction with UBQLN1 (By similarity). Mutant animals exhibit a dramatically reduced survival after weaning, with 50% of survival at 9 weeks (PubMed:18724932) or 17 weeks (PubMed:15254239). In 6-8 week old animals, multiple organs show extensive inflammation. The most severe diffuse lymphocytic infiltration occurs in the heart, followed by the lung, the liver, the smooth muscle of the uterus and the salivary gland with periductal infiltration. Other tissues exhibit only minimal to mild lymphocytic infiltration (PubMed:24218451). The heart phenotype includes inflammatory myocarditis leading to progressive, often dilated, cardiomyopathy and circulatory failure. Enlargement of the spleen and lymph nodes is observed in less than 10% of old mice (over 1 year of age) (PubMed:15254239). Mutant animals have a reduced 3'-exonuclease activity. They accumulate ssDNA from endogenous retroelements and produce high levels of autoantibodies. Do not show an increase in spontaneous mutation frequency or cancer incidence. Double knockout of TREX1 and either IRF3, IFNAR1 or RAG2 fully rescues the TREX1 single knockout phenotype (PubMed:18724932). Belongs to the exonuclease superfamily. TREX family.