Trex1 Exonuclease Degrades ssDNA to Prevent Chronic Checkpoint Activation and Autoimmune Disease

Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
Cell (Impact Factor: 32.24). 12/2007; 131(5):873-86. DOI: 10.1016/j.cell.2007.10.017
Source: PubMed


Trex1 is the major 3' DNA exonuclease in mammalian cells, and mutations in the human TREX1 gene can cause Aicardi-Goutières syndrome, characterized by perturbed immunity. Similarly, Trex1(-/-) mice have an autoinflammatory phenotype; however, the mechanism of Trex1-deficient disease is unknown. We report that Trex1, ordinarily associated with the endoplasmic reticulum (ER), relocalizes to the S phase nucleus after gamma irradiation or hydroxyurea treatment. Notably, Trex1-deficient cells show defective G1/S transition and chronic ATM-dependent checkpoint activation, even in the absence of exogenous stress, correlating with persistent single-stranded DNA molecules produced in S phase, which accumulate in the ER. Our data indicate that Trex1 acts on a single-stranded DNA polynucleotide species generated from processing of aberrant replication intermediates to attenuate DNA damage checkpoint signaling and prevent pathological immune activation.

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Available from: Yun-Gui Yang
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    • "The list of enzymes, including various DNA glycosylases, alkyltransferases, endo-and exonucleases identified and characterized by Tomas Lindahl's group for various aspects of DNA metabolisms is nearly endless. Some examples are early studies on uracil [21], hypoxanthine [22], processing of DNA 5 0 terminal ends [23], poly(ADP-ribose) [24], and the DNA ligases that complete various repair pathways by sealing nicks in DNA [26] [27], as well as more recent studies on Trex1-mediated degradation of single-stranded (ssDNA) [25]. Several mammalian repair enzymes were further characterized by the design of gene-targeted mice [28] [29] [30] [31]. "
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    ABSTRACT: Tomas Lindahl completed his medical studies at Karolinska Institute in 1970. Yet, his work has always been dedicated to unraveling fundamental mechanisms of DNA decay and DNA repair. His research is characterized with groundbreaking discoveries on the instability of our genome, the identification of novel DNA repair activities, the characterization of DNA repair pathways, and the association to diseases, throughout his 40 years of scientific career.
    Full-text · Article · Dec 2015
    • "In AGS the diminished TREX1 DNase activity leads to accumulation of self-DNA from replication debris (Yang et al., 2007) or endogenous retroelements (Stetson et al., 2008), probably contributing to sterile inflammation. However, such etiology does not explain disease caused by C-terminal frameshift mutations. "
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    ABSTRACT: TREX1 is an endoplasmic reticulum (ER)-associated negative regulator of innate immunity. TREX1 mutations are associated with autoimmune and autoinflammatory diseases. Biallelic mutations abrogating DNase activity cause autoimmunity by allowing immunogenic self-DNA to accumulate, but it is unknown how dominant frameshift (fs) mutations that encode DNase-active but mislocalized proteins cause disease. We found that the TREX1 C terminus suppressed immune activation by interacting with the ER oligosaccharyltransferase (OST) complex and stabilizing its catalytic integrity. C-terminal truncation of TREX1 by fs mutations dysregulated the OST complex, leading to free glycan release from dolichol carriers, as well as immune activation and autoantibody production. A connection between OST dysregulation and immune disorders was demonstrated in Trex1(-/-) mice, TREX1-V235fs patient lymphoblasts, and TREX1-V235fs knock-in mice. Inhibiting OST with aclacinomycin corrects the glycan and immune defects associated with Trex1 deficiency or fs mutation. This function of the TREX1 C terminus suggests a potential therapeutic option for TREX1-fs mutant-associated diseases. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Immunity
    • "Indeed, the lack of TREX1 in patients with AGS is thought to lead to an accumulation of HERV DNA in the cytoplasm, ultimately inducing a type I IFN response (Stetson et al., 2008). Thus, TREX1 deficiency could cause chronic activation of DNA-sensing PRRs, accounting for the inflammatory disease and elevated type I IFN observed in these patients (Yang et al., 2007). Interestingly, the use of reverse transcriptase inhibitors in TREX1 knockout mice resulted in improved survival and reduced markers of inflammation in autoimmune myocarditis (Beck-Engeser et al., 2011). "
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    ABSTRACT: The human genome comprises 8 % endogenous retroviruses (ERVs), the majority of which are defective due to deleterious mutations. Nonetheless, transcripts of ERVs are found in most tissues, and these transcripts could either be reverse transcribed to generate ssDNA or expressed to generate proteins. Thus, the expression of ERVs could produce nucleic acids or proteins with viral signatures, much like the pathogen-associated molecular patterns of exogenous viruses, which would enable them to be detected by the innate immune system. The activation of some pattern recognition receptors (PRRs) in response to ERVs has been described in mice and in the context of human autoimmune diseases. Here, we review the evidence for detection of ERVs by PRRs and the resultant activation of innate immune signalling. This is an emerging area of research within the field of innate antiviral immunity, showing how ERVs could initiate immune signalling pathways and might have implications for numerous inflammatory diseases. © 2015 The Authors.
    No preview · Article · Dec 2014 · Journal of General Virology
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