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, Oct 05, 2015
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    • "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.
    Immunity 08/2015; DOI:10.1016/j.immuni.2015.07.022 · 21.56 Impact Factor
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    • "Interestingly, unrepaired or irreparable DNA has been found to relocalize to the nuclear periphery (Nagai et al., 2008; Oza et al., 2009), suggesting that it may be segregated from replicating DNA for clearance. These studies—along with those in Trex1 À/À cells (Stetson et al., 2008; Yang et al., 2007)—are consistent with our findings. Testing the in vivo impact of autonomous damaged DNA on inflammation is not feasible at this time because we cannot eliminate the effects of extracellular DNA in animals. "
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    ABSTRACT: Deficiencies in DNA-degrading nucleases lead to accumulation of self DNA and induction of autoimmunity in mice and in monogenic and polygenic human diseases. However, the sources of DNA and the mechanisms that trigger immunity remain unclear. We analyzed mice deficient for the lysosomal nuclease Dnase2a and observed elevated levels of undegraded DNA in both phagocytic and nonphagocytic cells. In nonphagocytic cells, the excess DNA originated from damaged DNA in the nucleus based on colocalization studies, live-cell imaging, and exacerbation by DNA-damaging agents. Removal of damaged DNA by Dnase2a required nuclear export and autophagy-mediated delivery of the DNA to lysosomes. Finally, DNA was found to accumulate in Dnase2a(-/-) or autophagy-deficient cells and induce inflammation via the Sting cytosolic DNA-sensing pathway. Our results reveal a cell-autonomous process for removal of damaged nuclear DNA with implications for conditions with elevated DNA damage, such as inflammation, cancer, and chemotherapy.
    Cell Reports 10/2014; 9(1). DOI:10.1016/j.celrep.2014.08.074 · 8.36 Impact Factor
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    • "Trex1–/– mice develop multiple-organ inflammation, as well as autoantibodies, and succumb to inflammation burden early in age (Gall et al., 2012). Self-DNA from endogenous retroelements (Stetson et al., 2008) or DNA replication debris (Yang et al., 2007) are among the likely causes of inflammation in Trex1–/– mice. Inflammatory phenotypes can be rescued by eliminating essential components of the known DNA sensing pathway (e.g., Irf3–/–, Sting–/–), functionally linking the DNase function of TREX1 to disease (Stetson et al., 2008; Gall et al., 2012). "
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    ABSTRACT: Innate immune recognition is crucial for host responses against viral infections, including infection by human immunodeficiency virus 1 (HIV-1). Human cells detect such invading pathogens with a collection of pattern recognition receptors that activate the production of antiviral proteins, such as the cytokine interferon-type I, to initiate antiviral responses immediately as well as the adaptive immune response for long-term protection. To establish infection in the host, many viruses have thus evolved strategies for subversion of these mechanisms of innate immunity. For example, acute infection by HIV-1 and other retroviruses have long been thought to be non-immunogenic, signifying suppression of host defenses by these pathogens. Studies in the past few years have begun to uncover a multifaceted scheme of how HIV-1 evades innate immune detection, especially of its DNA, by exploiting host proteins. This review will discuss the host mechanisms of HIV-1 DNA sensing and viral immune evasion, with a particular focus on TREX1, three prime repair exonuclease 1, a host 3' exonuclease (also known as DNase III).
    Frontiers in Microbiology 04/2014; 5:193. DOI:10.3389/fmicb.2014.00193 · 3.99 Impact Factor
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