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:10393201, PubMed:17293595). 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). 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. Homodimer (By similarity). 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). Retained in the cytoplasm through the C-terminal region (By similarity). 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). Detected in thymus, spleen, liver, brain, heart, small intestine and colon. Ubiquitinated, but not targeted to proteasomal degradation. Ubiquitination may be important for interaction with UBQLN1. The disease is caused by variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. Enhanced immune sensing of oxidized DNA may be involved in the phototoxicity experienced by SLE patients. Exposure to UV-light produces DNA oxidative damage. Oxidized DNA being a poor TREX1 substrate, it accumulates in skin, leading to enhanced auto-immune reactivity and eventually skin lesions (PubMed:23993650). The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Belongs to the exonuclease superfamily. TREX family. The gene for this protein is either identical to or adjacent to that of ATRIP. Some of the mRNAs that encode ATRIP also encode TREX1 in another reading frame. Truncated N-terminus. Truncated N-terminus.