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

doi:10.1016/j.cell.2007.08.029

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

Cell Biology

Research output: Contribution to journal › Article › peer-review

123 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 language	English (US)
Pages (from-to)	863-877
Number of pages	15
Journal	Cell
Volume	130
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2007.08.029
State	Published - Sep 7 2007

Keywords

CELLBIO
CELLCYCLE
DNA

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2007.08.029

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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

Schaetzlein, S, Kodandaramireddy, NR, Ju, Z, Lechel, A, Stepczynska, A, Lilli, DR, Clark, AB, Rudolph, C, Wei, K, Schlegelberger, B, Schirmacher, P, Kunkel, TA, Greenberg, RA, Edelmann, W & Rudolph, KL 2007, 'Exonuclease-1 Deletion Impairs DNA Damage Signaling and Prolongs Lifespan of Telomere-Dysfunctional Mice', Cell, vol. 130, no. 5, pp. 863-877. https://doi.org/10.1016/j.cell.2007.08.029

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title = "Exonuclease-1 Deletion Impairs DNA Damage Signaling and Prolongs Lifespan of Telomere-Dysfunctional Mice",

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.",

keywords = "CELLBIO, CELLCYCLE, DNA",

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

note = "Funding Information: K.L.R. was generously supported by the Deutsche Forschungsgemeinschaft (Heisenberg Professorship to K.L.R.: Ru 745/8-1, Ru745 4-1, KFO119, SFB 738, REBIRTH), the Deutsche Krebshilfe e.V. (10-2236-Ru 2), the Roggenbuck-Stiftung, the Wilhelm-Sander-Stiftung, and the Fritz-Thyssen Stiftung. A.B.C. and T.A.K. are supported by intramural research programs of the NIH and NIEHS. W.E. is funded by the NCI (R01CA093484). ",

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doi = "10.1016/j.cell.2007.08.029",

language = "English (US)",

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AU - Schaetzlein, Sonja

AU - Kodandaramireddy, N. R.

AU - Ju, Zhenyu

AU - Lechel, Andre

AU - Stepczynska, Anna

AU - Lilli, Dana R.

AU - Clark, Alan B.

AU - Rudolph, Cornelia

AU - Wei, Kaichun

AU - Schlegelberger, Brigitte

AU - Schirmacher, Peter

AU - Kunkel, Thomas A.

AU - Greenberg, Roger A.

AU - Edelmann, Winfried

AU - Rudolph, K. Lenhard

N1 - Funding Information: K.L.R. was generously supported by the Deutsche Forschungsgemeinschaft (Heisenberg Professorship to K.L.R.: Ru 745/8-1, Ru745 4-1, KFO119, SFB 738, REBIRTH), the Deutsche Krebshilfe e.V. (10-2236-Ru 2), the Roggenbuck-Stiftung, the Wilhelm-Sander-Stiftung, and the Fritz-Thyssen Stiftung. A.B.C. and T.A.K. are supported by intramural research programs of the NIH and NIEHS. W.E. is funded by the NCI (R01CA093484).

PY - 2007/9/7

Y1 - 2007/9/7

N2 - 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.

AB - 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.

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JF - Cell

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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