The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis

J Falck, Niels Mailand, R G Syljuåsen, J Bartek, J Lukas

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Abstract

When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the IR-induced S-phase checkpoint cause 'radioresistant DNA synthesis', a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia, a disease caused by mutations in the ATM gene. The Cdc25A phosphatase activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) and Cdc25A, and implicate this mechanism in controlling the S-phase checkpoint. We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. An IR-induced loss of Cdc25A protein prevents dephosphorylation of Cdk2 and leads to a transient blockade of DNA replication. We also show that tumour-associated Chk2 alleles cannot bind or phosphorylate Cdc25A, and that cells expressing these Chk2 alleles, elevated Cdc25A or a Cdk2 mutant unable to undergo inhibitory phosphorylation (Cdk2AF) fail to inhibit DNA synthesis when irradiated. These results support Chk2 as a candidate tumour suppressor, and identify the ATM-Chk2-Cdc25A-Cdk2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.

Original languageEnglish
JournalNature
Volume410
Issue number6830
Pages (from-to)842-7
Number of pages6
ISSN0028-0836
DOIs
Publication statusPublished - 12 Apr 2001
Externally publishedYes

Keywords

  • Alleles
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Line
  • Checkpoint Kinase 2
  • DNA Replication
  • DNA-Binding Proteins
  • Humans
  • Mice
  • Phosphorylation
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Radiation Tolerance
  • Radiation, Ionizing
  • S Phase
  • Serine
  • Signal Transduction
  • Transfection
  • Tumor Suppressor Proteins
  • cdc25 Phosphatases

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