8vl7

Structural highlights

Disease

TREX1_HUMAN Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Familial Chilblain lupus;Systemic lupus erythematosus;Aicardi-Goutieres syndrome. 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).^[1] 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.

Function

TREX1_HUMAN 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).^{[2] [3] [4] [5] [6] [7] [8]}

References

1. ↑ Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, Tuting T, Hartmann G, Barchet W. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity. 2013 Sep 19;39(3):482-95. doi: 10.1016/j.immuni.2013.08.004. Epub 2013 , Aug 29. PMID:23993650 doi:http://dx.doi.org/10.1016/j.immuni.2013.08.004
2. ↑ Mazur DJ, Perrino FW. Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3'-->5' exonucleases. J Biol Chem. 1999 Jul 9;274(28):19655-60. PMID:10391904
3. ↑ Hoss M, Robins P, Naven TJ, Pappin DJ, Sgouros J, Lindahl T. A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein. EMBO J. 1999 Jul 1;18(13):3868-75. doi: 10.1093/emboj/18.13.3868. PMID:10393201 doi:http://dx.doi.org/10.1093/emboj/18.13.3868
4. ↑ Chowdhury D, Beresford PJ, Zhu P, Zhang D, Sung JS, Demple B, Perrino FW, Lieberman J. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol Cell. 2006 Jul 7;23(1):133-42. doi: 10.1016/j.molcel.2006.06.005. PMID:16818237 doi:http://dx.doi.org/10.1016/j.molcel.2006.06.005
5. ↑ de Silva U, Choudhury S, Bailey SL, Harvey S, Perrino FW, Hollis T. The crystal structure of TREX1 explains the 3' nucleotide specificity and reveals a polyproline II helix for protein partnering. J Biol Chem. 2007 Apr 6;282(14):10537-43. Epub 2007 Feb 9. PMID:17293595 doi:10.1074/jbc.M700039200
6. ↑ Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell. 2007 Nov 30;131(5):873-86. doi: 10.1016/j.cell.2007.10.017. PMID:18045533 doi:http://dx.doi.org/10.1016/j.cell.2007.10.017
7. ↑ Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, Tuting T, Hartmann G, Barchet W. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity. 2013 Sep 19;39(3):482-95. doi: 10.1016/j.immuni.2013.08.004. Epub 2013 , Aug 29. PMID:23993650 doi:http://dx.doi.org/10.1016/j.immuni.2013.08.004
8. ↑ Mohr L, Toufektchan E, von Morgen P, Chu K, Kapoor A, Maciejowski J. ER-directed TREX1 limits cGAS activation at micronuclei. Mol Cell. 2021 Feb 18;81(4):724-738.e9. doi: 10.1016/j.molcel.2020.12.037. Epub, 2021 Jan 20. PMID:33476576 doi:http://dx.doi.org/10.1016/j.molcel.2020.12.037