STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage

J Cell Sci. 2005 Apr 15;118(Pt 8):1629-39. doi: 10.1242/jcs.01728. Epub 2005 Mar 22.

Abstract

STAT-1 plays a role in mediating stress responses to various stimuli and has also been implied to be a tumour suppressor. Here, we report that STAT-1-deficient cells have defects both in intra-S-phase and G2-M checkpoints in response to DNA damage. Interestingly, STAT-1-deficient cells showed reduced Chk2 phosphorylation on threonine 68 (Chk2(-T68)) following DNA damage, suggesting that STAT-1 might function in the ATM-Chk2 pathway. Moreover, the defects in Chk2(-T68) phosphorylation in STAT-1-deficient cells also correlated with reduced degradation of Cdc25A compared with STAT-1-expressing cells after DNA damage. We also show that STAT-1 is required for ATM-dependent phosphorylation of NBS1 and p53 but not for BRCA1 or H2AX phosphorylation following DNA damage. Expression levels of BRCT mediator/adaptor proteins MDC1 and 53BP1, which are required for ATM-mediated pathways, are reduced in cells lacking STAT-1. Enforced expression of MDC1 into STAT-1-deficient cells restored ATM-mediated phosphorylation of downstream substrates. These results imply that STAT-1 plays a crucial role in the DNA-damage-response by regulating the expression of 53BP1 and MDC1, factors known to be important for mediating ATM-dependent checkpoint pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Checkpoint Kinase 2
  • Chromosomal Proteins, Non-Histone
  • DNA Damage / physiology*
  • DNA Repair / physiology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation / genetics
  • Genes, cdc / physiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • STAT1 Transcription Factor
  • Signal Transduction / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Tumor Suppressor p53-Binding Protein 1
  • cdc25 Phosphatases / genetics
  • cdc25 Phosphatases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • MDC1 protein, human
  • NBN protein, human
  • Nuclear Proteins
  • Phosphoproteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Stat1 protein, mouse
  • TP53BP1 protein, human
  • Trans-Activators
  • Trp53bp1 protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Tumor Suppressor p53-Binding Protein 1
  • 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