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The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor.

Publication ,  Journal Article
Morales, M; Theunissen, J-WF; Kim, CFB; Kitagawa, R; Kastan, MB; Petrini, JHJ
Published in: Genes Dev
December 15, 2005

Genetic and cytologic data from Saccharomyces cerevisiae and mammals implicate the Mre11 complex, consisting of Mre11, Rad50, and Nbs1, as a sensor of DNA damage, and indicate that the complex influences the activity of ataxia-telangiectasia mutated (ATM) in the DNA damage response. Rad50(S/S) mice exhibit precipitous apoptotic attrition of hematopoietic cells. We generated ATM- and Chk2-deficient Rad50(S/S) mice and found that Rad50(S/S) cellular attrition was strongly ATM and Chk2 dependent. The hypomorphic Mre11(ATLD1) and Nbs1(Delta)(B) alleles conferred similar rescue of Rad50(S/S)-dependent hematopoietic failure. These data indicate that the Mre11 complex activates an ATM-Chk2-dependent apoptotic pathway. We find that apoptosis and cell cycle checkpoint activation are parallel outcomes of the Mre11 complex-ATM pathway. Conversely, the Rad50(S) mutation mitigated several phenotypic features of ATM deficiency. We propose that the Rad50(S) allele is hypermorphic for DNA damage signaling, and that the resulting constitutive low-level activation of the DNA damage response accounts for the partial suppression of ATM deficiency in Rad50(S/S) Atm(-/-) mice.

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Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

December 15, 2005

Volume

19

Issue

24

Start / End Page

3043 / 3054

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Signal Transduction
  • Protein Serine-Threonine Kinases
  • Mice, Knockout
  • Mice
  • Male
  • MRE11 Homologue Protein
  • Hematopoietic Stem Cells
  • Hematopoiesis
  • Gene Expression Regulation
 

Citation

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Morales, M., Theunissen, J.-W., Kim, C. F. B., Kitagawa, R., Kastan, M. B., & Petrini, J. H. J. (2005). The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor. Genes Dev, 19(24), 3043–3054. https://doi.org/10.1101/gad.1373705
Morales, Monica, Jan-Willem F. Theunissen, Carla F Bender Kim, Risa Kitagawa, Michael B. Kastan, and John H. J. Petrini. “The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor.Genes Dev 19, no. 24 (December 15, 2005): 3043–54. https://doi.org/10.1101/gad.1373705.
Morales M, Theunissen J-WF, Kim CFB, Kitagawa R, Kastan MB, Petrini JHJ. The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor. Genes Dev. 2005 Dec 15;19(24):3043–54.
Morales, Monica, et al. “The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor.Genes Dev, vol. 19, no. 24, Dec. 2005, pp. 3043–54. Pubmed, doi:10.1101/gad.1373705.
Morales M, Theunissen J-WF, Kim CFB, Kitagawa R, Kastan MB, Petrini JHJ. The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor. Genes Dev. 2005 Dec 15;19(24):3043–3054.

Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

December 15, 2005

Volume

19

Issue

24

Start / End Page

3043 / 3054

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Signal Transduction
  • Protein Serine-Threonine Kinases
  • Mice, Knockout
  • Mice
  • Male
  • MRE11 Homologue Protein
  • Hematopoietic Stem Cells
  • Hematopoiesis
  • Gene Expression Regulation