scholarly journals DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Claire Vanpouille-Box ◽  
Amandine Alard ◽  
Molykutty J. Aryankalayil ◽  
Yasmeen Sarfraz ◽  
Julie M. Diamond ◽  
...  
Keyword(s):  
Exonuclease Trex1

C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

2007 ◽  
Vol 39 (9) ◽  
pp. 1068-1070 ◽  
Author(s):  
Anna Richards ◽  
Arn M J M van den Maagdenberg ◽  
Joanna C Jen ◽  
David Kavanagh ◽  
Paula Bertram ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Exonuclease Trex1

scholarly journals Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS

2019 ◽  
Vol 216 (5) ◽  
pp. 1199-1213 ◽  
Author(s):  
Matthieu Gratia ◽  
Mathieu P. Rodero ◽  
Cécile Conrad ◽  
Elias Bou Samra ◽  
Mathieu Maurin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Genome Instability ◽  
Bloom Syndrome ◽  
Innate Immune ◽  
Genome Integrity ◽  
Immune Sensing ◽  
Syndrome Protein ◽  
Innate Immune Sensing ◽  
Exonuclease Trex1

Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-DNA inside cells poses a risk of triggering unchecked immune responses. The mechanisms limiting induction of inflammation by self-DNA are poorly understood. BLM RecQ–like helicase is essential for genome integrity and is deficient in Bloom syndrome (BS), a rare genetic disease characterized by genome instability, accumulation of micronuclei, susceptibility to cancer, and immunodeficiency. Here, we show that BLM-deficient fibroblasts show constitutive up-regulation of inflammatory interferon-stimulated gene (ISG) expression, which is mediated by the cGAS–STING–IRF3 cytosolic DNA–sensing pathway. Increased DNA damage or down-regulation of the cytoplasmic exonuclease TREX1 enhances ISG expression in BLM-deficient fibroblasts. cGAS-containing cytoplasmic micronuclei are increased in BS cells. Finally, BS patients demonstrate elevated ISG expression in peripheral blood. These results reveal that BLM limits ISG induction, thus connecting DNA damage to cellular innate immune response, which may contribute to human pathogenesis.

scholarly journals New roles for the major human 3′-5′ exonuclease TREX1 in human disease

Cell Cycle ◽  
2008 ◽  
Vol 7 (12) ◽  
pp. 1718-1725 ◽  
Author(s):  
David Kavanagh ◽  
Dirk Spitzer ◽  
Parul Kothari ◽  
Aisha Shaikh ◽  
M. Kathryn Liszewski ◽  
...  
Keyword(s):  
Human Disease ◽  
Exonuclease Trex1

scholarly journals Human DNA Exonuclease TREX1 Is Also an Exoribonuclease That Acts on Single-stranded RNA

2015 ◽  
Vol 290 (21) ◽  
pp. 13344-13353 ◽  
Author(s):  
Fenghua Yuan ◽  
Tanmay Dutta ◽  
Ling Wang ◽  
Lei Song ◽  
Liya Gu ◽  
...  
Keyword(s):  
Human Dna ◽  
Exonuclease Trex1

scholarly journals The Exonuclease TREX1 Is in the SET Complex and Acts in Concert with NM23-H1 to Degrade DNA during Granzyme A-Mediated Cell Death

2006 ◽  
Vol 23 (1) ◽  
pp. 133-142 ◽  
Author(s):  
Dipanjan Chowdhury ◽  
Paul J. Beresford ◽  
Pengcheng Zhu ◽  
Dong Zhang ◽  
Jung-Suk Sung ◽  
...  
Keyword(s):  
Cell Death ◽  
Granzyme A ◽  
Exonuclease Trex1

scholarly journals The Exonuclease Trex1 Restrains Macrophage Proinflammatory Activation

2013 ◽  
Vol 191 (12) ◽  
pp. 6128-6135 ◽  
Author(s):  
Selma Pereira-Lopes ◽  
Teja Celhar ◽  
Gloria Sans-Fons ◽  
Maria Serra ◽  
Anna-Marie Fairhurst ◽  
...  
Keyword(s):  
Exonuclease Trex1

scholarly journals Structure of the Dimeric Exonuclease TREX1 in Complex with DNA Displays a Proline-rich Binding Site for WW Domains

2007 ◽  
Vol 282 (19) ◽  
pp. 14547-14557 ◽  
Author(s):  
Marina Brucet ◽  
Jordi Querol-Audí ◽  
Maria Serra ◽  
Ximena Ramirez-Espain ◽  
Kamila Bertlik ◽  
...  
Keyword(s):  
Binding Site ◽  
Ww Domains ◽  
Exonuclease Trex1

scholarly journals Exonuclease TREX1 also Has a Sweet Tooth

Immunity ◽  
2015 ◽  
Vol 43 (3) ◽  
pp. 411-413 ◽  
Author(s):  
Winfried Barchet ◽  
Thomas Zillinger
Keyword(s):  
Exonuclease Trex1

The 3'-5' Exonuclease, TREX1, Interacts with Poly(ADP-ribose) Polymerase-1 (PARP1) in Response to DNA Damage

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1046-1046
Author(s):  
Takuya Miyazaki ◽  
Yong-Soo Kim ◽  
Jeong-Heon Yoon ◽  
Hongsheng Wang ◽  
Herbert C. Morse
Keyword(s):  
Dna Damage ◽  
Autoimmune Diseases ◽  
Dna Damage Response ◽  
Molecular Mechanisms ◽  
Mutant Protein ◽  
Dependent Manner ◽  
Autoantibody Production ◽  
Amino Terminal ◽  
Damage Response ◽  
Exonuclease Trex1

Abstract Abstract 1046 Background: Recognition of nucleic acids plays a key role in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). The major 3'-5' DNA exonuclease, TREX1, degrades single- and double-stranded DNA to minimize potential immune activation by persistent self or retroelement DNA. Mutations in the human TREX1gene have been linked to four diseases: SLE; Aicardi-Goutières syndrome (AGS); retinal vasculopathy and cerebral leukodystrophy (RVCL); and familial chilblain lupus (CBL). SLE, AGS and CBL have overlapping features characterized by expression of interferon-alpha and autoantibody production, but are distinct clinical conditions. RVCL is a non-inflammatory endotheliopathy. Methods: As part of our efforts to determine the molecular mechanisms underlying TREX1 involvement in the pathogenesis of these diseases, we identified a novel TREX1-binding partner protein by Mass Spectrometry and Co-Immunoprecipitation (Co-IP) assays. We examined the interaction domains and the effects of mutations in TREX1 associated with these diseases. Results: We found that TREX1 interacted with poly(ADP-ribose) polymerase-1 (PARP1), a nuclear DNA repair enzyme involved in the DNA damage response. The interaction domain of PARP1 was mapped to the amino-terminal zinc finger domains. Subcellular localization analysis showed that TREX1 normally localized to the cytoplasm and cytomembranes, but translocated to the nucleus (with some bound to chromatin) in response to sublethal DNA damage. Co-IP assays revealed that the interaction was increased following DNA damage in concert with the post-translational PARlation of PARP1. Functional studies showed that TREX1 induced the PARlation of PARP1 in a TREX1 dose-dependent manner. Furthermore, siRNA knockdown of TREX1 promoted PARP1 cleavage and loss of PARP1 enzymatic activity, resulting in the induction of apoptosis. We further analyzed the effects of TREX1-PARP1 interaction in relation to the pathogenesis of AGS or RVCL. Co-IP assays revealed that the RVCL-related TREX1-mutant protein, V235fs, bound to PARP1 as well as wild-type TREX1, whereas the AGS-related R114H mutant protein did not bind PARP1. Conclusion: These findings demonstrate that TREX1 contributes to the regulation of PARP1 in the DNA damage response and that mutation-induced alterations in the function of TREX1 may be a factor in the development or progression of these autoimmune diseases by affecting PARP1 activity. Disclosures: No relevant conflicts of interest to declare.

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