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Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11.

Publication ,  Journal Article
Chen, C; Zhang, L; Huang, N-J; Huang, B; Kornbluth, S
Published in: Proceedings of the National Academy of Sciences of the United States of America
December 2013

Ataxia telangiectasia mutant (ATM) is an S/T-Q-directed kinase that is critical for the cellular response to double-stranded breaks (DSBs) in DNA. Following DNA damage, ATM is activated and recruited by the MRN protein complex [meiotic recombination 11 (Mre11)/DNA repair protein Rad50/Nijmegen breakage syndrome 1 proteins] to sites of DNA damage where ATM phosphorylates multiple substrates to trigger cell-cycle arrest. In cancer cells, this regulation may be faulty, and cell division may proceed even in the presence of damaged DNA. We show here that the ribosomal s6 kinase (Rsk), often elevated in cancers, can suppress DSB-induced ATM activation in both Xenopus egg extracts and human tumor cell lines. In analyzing each step in ATM activation, we have found that Rsk targets loading of MRN complex components onto DNA at DSB sites. Rsk can phosphorylate the Mre11 protein directly at S676 both in vitro and in intact cells and thereby can inhibit the binding of Mre11 to DNA with DSBs. Accordingly, mutation of S676 to Ala can reverse inhibition of the response to DSBs by Rsk. Collectively, these data point to Mre11 as an important locus of Rsk-mediated checkpoint inhibition acting upstream of ATM activation.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

December 2013

Volume

110

Issue

51

Start / End Page

20605 / 20610

Related Subject Headings

  • Xenopus laevis
  • Xenopus Proteins
  • Ribosomal Protein S6 Kinases
  • Nuclear Proteins
  • Mutation, Missense
  • MRE11 Homologue Protein
  • Humans
  • Hela Cells
  • HeLa Cells
  • DNA-Binding Proteins
 

Citation

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Chen, C., Zhang, L., Huang, N.-J., Huang, B., & Kornbluth, S. (2013). Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11. Proceedings of the National Academy of Sciences of the United States of America, 110(51), 20605–20610. https://doi.org/10.1073/pnas.1306328110
Chen, Chen, Liguo Zhang, Nai-Jia Huang, Bofu Huang, and Sally Kornbluth. “Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11.Proceedings of the National Academy of Sciences of the United States of America 110, no. 51 (December 2013): 20605–10. https://doi.org/10.1073/pnas.1306328110.
Chen C, Zhang L, Huang N-J, Huang B, Kornbluth S. Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11. Proceedings of the National Academy of Sciences of the United States of America. 2013 Dec;110(51):20605–10.
Chen, Chen, et al. “Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11.Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 51, Dec. 2013, pp. 20605–10. Epmc, doi:10.1073/pnas.1306328110.
Chen C, Zhang L, Huang N-J, Huang B, Kornbluth S. Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11. Proceedings of the National Academy of Sciences of the United States of America. 2013 Dec;110(51):20605–20610.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

December 2013

Volume

110

Issue

51

Start / End Page

20605 / 20610

Related Subject Headings

  • Xenopus laevis
  • Xenopus Proteins
  • Ribosomal Protein S6 Kinases
  • Nuclear Proteins
  • Mutation, Missense
  • MRE11 Homologue Protein
  • Humans
  • Hela Cells
  • HeLa Cells
  • DNA-Binding Proteins