Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease.

Abstract	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.
Authors	Yun-Gui Yang, Tomas Lindahl, Deborah E Barnes
Journal	Cell (Cell) Vol. 131 Issue 5 Pg. 873-86 (Nov 30 2007) ISSN: 0092-8674 [Print] United States
PMID	18045533 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cell Cycle Proteins DNA, Single-Stranded DNA-Binding Proteins Phosphoproteins Proteins Tumor Suppressor Proteins ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases Exodeoxyribonucleases three prime repair exonuclease 1 Hydroxyurea
Topics	Animals Ataxia Telangiectasia Mutated Proteins Autoimmune Diseases (etiology, genetics) Cell Cycle (drug effects, genetics, radiation effects) Cell Cycle Proteins (metabolism, physiology) Cell Nucleus (metabolism, radiation effects) Cells, Cultured DNA Damage (genetics) DNA Replication (physiology) DNA, Single-Stranded (metabolism) DNA-Binding Proteins (physiology) Exodeoxyribonucleases (genetics, metabolism, physiology) Gamma Rays Genes, cdc (physiology) Humans Hydroxyurea (pharmacology) Mice Mice, Knockout Phosphoproteins (genetics, metabolism, physiology) Protein Serine-Threonine Kinases (physiology) Proteins (genetics) Signal Transduction (drug effects, radiation effects) Tumor Suppressor Proteins (physiology)

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