Trex1 Exonuclease Degrades ssDNA to Prevent Chronic Checkpoint Activation and Autoimmune Disease

Cell. 2007 Nov 30;131(5):873-86. doi: 10.1016/j.cell.2007.10.017.

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