Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease.
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.
Yang
Yun-Gui
YG
Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
Lindahl
Tomas
T
Barnes
Deborah E
DE
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001327:Autoimmune Diseases / Q000209:etiology / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000502:physiology; D004277:DNA, Single-Stranded / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005720:Gamma Rays; D018816:Genes, cdc / Q000502:physiology; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000502:physiology
D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; D006918:Hydroxyurea