Abstract
Activating transcription factor 2 (ATF2) is regulated by JNK/p38 in response to stress. Here, we demonstrate that the protein kinase ATM phosphorylates ATF2 on serines 490 and 498 following ionizing radiation (IR). Phosphoantibodies to ATF2(490/8) reveal dose- and time-dependent phosphorylation of ATF2 by ATM that results in its rapid colocalization with gamma-H2AX and MRN components into IR-induced foci (IRIF). Inhibition of ATF2 expression decreased recruitment of Mre11 to IRIF, abrogated S phase checkpoint, reduced activation of ATM, Chk1, and Chk2, and impaired radioresistance. ATF2 requires neither JNK/p38 nor its DNA binding domain for recruitment to IRIF and the S phase checkpoint. Our findings identify a role for ATF2 in the DNA damage response that is uncoupled from its transcriptional activity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activating Transcription Factor 2
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Amino Acid Sequence
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Animals
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Antibodies, Phospho-Specific / metabolism
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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
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Checkpoint Kinase 1
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Checkpoint Kinase 2
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism*
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DNA Damage*
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DNA Repair
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DNA Repair Enzymes
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Fibroblasts / cytology
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Fibroblasts / physiology
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Histones / metabolism
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Humans
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MRE11 Homologue Protein
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Mice
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Molecular Sequence Data
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Nuclear Proteins / metabolism
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Phosphorylation
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Radiation, Ionizing
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Sequence Alignment
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Serine / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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ATF2 protein, human
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Activating Transcription Factor 2
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Antibodies, Phospho-Specific
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Atf2 protein, mouse
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Cell Cycle Proteins
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Cyclic AMP Response Element-Binding Protein
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DNA-Binding Proteins
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H2AX protein, human
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Histones
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MRE11 protein, human
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Mre11a protein, mouse
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NBN protein, human
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Nuclear Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Serine
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Protein Kinases
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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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CHEK1 protein, human
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CHEK2 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases
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MRE11 Homologue Protein
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DNA Repair Enzymes