ATM-dependent Phosphorylation of ATF2 Is Required for the DNA Damage Response

Mol Cell. 2005 May 27;18(5):577-87. doi: 10.1016/j.molcel.2005.04.015.

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

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factor 2
  • Amino Acid Sequence
  • Animals
  • Antibodies, Phospho-Specific / metabolism
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • DNA Damage*
  • DNA Repair
  • DNA Repair Enzymes
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Histones / metabolism
  • Humans
  • MRE11 Homologue Protein
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Radiation, Ionizing
  • Sequence Alignment
  • Serine / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Antibodies, Phospho-Specific
  • Atf2 protein, mouse
  • Cell Cycle Proteins
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • H2AX protein, human
  • Histones
  • MRE11 protein, human
  • Mre11a protein, mouse
  • NBN protein, human
  • Nuclear Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Serine
  • Protein Kinases
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • MRE11 Homologue Protein
  • DNA Repair Enzymes