The ATM-Chk2-Cdc25A Checkpoint Pathway Guards Against Radioresistant DNA Synthesis

Nature. 2001 Apr 12;410(6830):842-7. doi: 10.1038/35071124.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • Serine
  • Protein Kinases
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • CHEK2 protein, human
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • CDC25A protein, human
  • Cdc25a protein, mouse
  • cdc25 Phosphatases