Exonuclease-1 Deletion Impairs DNA Damage Signaling and Prolongs Lifespan of Telomere-Dysfunctional Mice

Sonja Schaetzlein, N. R. Kodandaramireddy, Zhenyu Ju, Andre Lechel, Anna Stepczynska, Dana R. Lilli, Alan B. Clark, Cornelia Rudolph, Kaichun Wei, Brigitte Schlegelberger, Peter Schirmacher, Thomas A. Kunkel, Roger A. Greenberg, Winfried Edelmann, K. Lenhard Rudolph

Research output: Contribution to journalArticle

113 Scopus citations

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 γ-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.

Original languageEnglish (US)
Pages (from-to)863-877
Number of pages15
JournalCell
Volume130
Issue number5
DOIs
StatePublished - Sep 7 2007

Keywords

  • CELLBIO
  • CELLCYCLE
  • DNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Schaetzlein, S., Kodandaramireddy, N. R., Ju, Z., Lechel, A., Stepczynska, A., Lilli, D. R., Clark, A. B., Rudolph, C., Wei, K., Schlegelberger, B., Schirmacher, P., Kunkel, T. A., Greenberg, R. A., Edelmann, W., & Rudolph, K. L. (2007). Exonuclease-1 Deletion Impairs DNA Damage Signaling and Prolongs Lifespan of Telomere-Dysfunctional Mice. Cell, 130(5), 863-877. https://doi.org/10.1016/j.cell.2007.08.029