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
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cells, Cultured
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Checkpoint Kinase 2
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Chromosomal Proteins, Non-Histone
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DNA Damage / physiology*
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DNA Repair / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation / genetics
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Genes, cdc / physiology*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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STAT1 Transcription Factor
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Signal Transduction / genetics
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Tumor Suppressor p53-Binding Protein 1
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cdc25 Phosphatases / genetics
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cdc25 Phosphatases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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MDC1 protein, human
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NBN protein, human
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Nuclear Proteins
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Phosphoproteins
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STAT1 Transcription Factor
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STAT1 protein, human
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Stat1 protein, mouse
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TP53BP1 protein, human
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Trans-Activators
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Trp53bp1 protein, mouse
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Tumor Suppressor p53-Binding Protein 1
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Checkpoint Kinase 2
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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CHEK2 protein, human
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases
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CDC25A protein, human
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Cdc25a protein, mouse
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cdc25 Phosphatases