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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Ataxia Telangiectasia Mutated Proteins
-
Autoimmune Diseases / etiology
-
Autoimmune Diseases / genetics*
-
Cell Cycle / drug effects
-
Cell Cycle / genetics
-
Cell Cycle / radiation effects
-
Cell Cycle Proteins / metabolism*
-
Cell Cycle Proteins / physiology
-
Cell Nucleus / metabolism
-
Cell Nucleus / radiation effects
-
Cells, Cultured
-
DNA Damage / genetics
-
DNA Replication / physiology
-
DNA, Single-Stranded / metabolism*
-
DNA-Binding Proteins / physiology
-
Exodeoxyribonucleases / genetics
-
Exodeoxyribonucleases / metabolism
-
Exodeoxyribonucleases / physiology*
-
Gamma Rays
-
Genes, cdc / physiology
-
Humans
-
Hydroxyurea / pharmacology
-
Mice
-
Mice, Knockout
-
Phosphoproteins / genetics
-
Phosphoproteins / metabolism
-
Phosphoproteins / physiology*
-
Protein Serine-Threonine Kinases / physiology
-
Proteins / genetics
-
Signal Transduction / drug effects
-
Signal Transduction / radiation effects
-
Tumor Suppressor Proteins / physiology
Substances
-
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