Browse the corpus

Three prime repair exonuclease 1 (TREX1) is a widely expressed protein that acts as part of the SET complex in granzyme A-mediated apoptosis to degrade single-stranded DNA. TREX1 encodes a 3'-exonuclease 1 protein that removes nucleotides from the 3' ends of DNA molecules to remove unneeded fragments that may form during DNA replication. The TREX1 gene has also been found to play a role in immune regulation and viral infection. Research has found that mutations in this gene correlate with many diseases, including Aicardi-Goutieres syndrome (AGS), systemic lupus erythematosus (SLE), familial chilblain lupus (FCL), Cree encephalitis, cryofibrinogenemia, and retinal vasculopathy with cerebral leukodystrophy (RVCL).[1] This topic outlines the features of these various diseases and describes the role of TREX1 genes in the pathophysiology of these diseases.

Studies have shown a clear mechanism by which TREX1 maintains the host's innate immune tolerance to cytosolic self-DNA. TREX1 mutations lead to the accumulation of self-DNA in the cytosol of TREX1-deficient cells. The persistence of the ssDNA species substrate of TREX1 triggers systemic inflammation and uncontrolled autoimmunity by chronic activation of checkpoint signaling and cGAS-STING-mediated type I interferon response.[4] TREX1 has a significant preference for special DNA sequences. Endogenous ssDNA species of 60 to 65 nucleotides, DNA viruses, and retroviruses are the sources of ssDNA species that could accumulate in TREX1-deficient cells.[10] Previous studies have shown that TREX1 gene deletion in mice leads to inflammatory myocarditis and shortened lifespan due to an interferon-dependent autoimmune response.[7] Recessive missense mutations in TREX1 are mostly associated with AGS, whereas dominant frame-shift mutations are predominantly associated with RVCL.[4] The encephalopathy in AGS and the cardiomyopathy of TREX1 null mice are both autoinflammatory responses. Increased interferon-alpha (IFN-α) levels in AGS and SLE are similar to antiviral immune responses.[10] Additionally, research has shown that the TREX1 is associated with the SET complex.[23] The SET complex is a DNA repair complex that is targeted by Granzyme A during caspase-independent T cell-mediated death.[24] TREX1 binds to the SET complex, translocates to the nucleus, and rapidly degrades 3′ ends of DNA during granzyme A-mediated cell death. Thus, TREX-1-deficient cells are relatively resistant to apoptosis.[10][23][25] Moreover, there are suggestions that there is a connection between chromothripsis in human cancer and TREX1-mediated chromosomal fragmentation in telomere crisis.[26] The distinct activities of TREX1, the variety of its nucleic acid substrates, its role in DNA degradation in dying cells[23], and the linkage of TREX1 to human cancer by chromosomal fragmentation in telomere crisis have made it recognizable as an important factor in the treatment of cancers.[26][27][28]