Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice

Cell. 2007 Sep 7;130(5):863-77. doi: 10.1016/j.cell.2007.08.029.

Abstract

Exonuclease-1 (EXO1) mediates checkpoint induction in response to telomere dysfunction in yeast, but it is unknown whether EXO1 has similar functions in mammalian cells. Here we show that deletion of the nuclease domain of Exo1 reduces accumulation of DNA damage and DNA damage signal induction in telomere-dysfunctional mice. Exo1 deletion improved organ maintenance and lifespan of telomere-dysfunctional mice but did not increase chromosomal instability or cancer formation. Deletion of Exo1 also ameliorated the induction of DNA damage checkpoints in response to gamma-irradiation and conferred cellular resistance to 6-thioguanine-induced DNA damage. Exo1 deletion impaired upstream induction of DNA damage responses by reducing ssDNA formation and the recruitment of Replication Protein A (RPA) and ATR at DNA breaks. Together, these studies provide evidence that EXO1 contributes to DNA damage signal induction in mammalian cells, and deletion of Exo1 can prolong survival in the context of telomere dysfunction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation
  • Chromosomal Instability
  • DNA Damage*
  • DNA, Single-Stranded / metabolism
  • Exodeoxyribonucleases / deficiency
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism*
  • Gamma Rays
  • Gene Deletion*
  • Gene Fusion
  • Genotype
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / radiation effects
  • Longevity* / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagens / pharmacology
  • Phenotype
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA / genetics
  • RNA / metabolism*
  • Replication Protein A / metabolism
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Signal Transduction* / radiation effects
  • Telomerase / deficiency
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Telomere / metabolism*
  • Thioguanine / pharmacology

Substances

  • Cell Cycle Proteins
  • DNA, Single-Stranded
  • Mutagens
  • Replication Protein A
  • telomerase RNA
  • RNA
  • Atr protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Telomerase
  • Exodeoxyribonucleases
  • exodeoxyribonuclease I
  • Thioguanine