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Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress

Jun Hayakawa1, Shalu Mittal, Yipeng Wang

  • 1Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, California 92121, USA.

Molecular Cell
|November 18, 2004
PubMed

Insights

The study reveals that cisplatin-induced DNA repair involves the activation of Jun kinases (JNKs), leading to the binding of ATF2 and c-Jun to specific gene promoters. This coordinated gene expression is crucial for the genotoxic stress response.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cellular Biology

Background:

  • Jun kinases (JNKs) play vital roles in cellular processes through the activation of AP-1 components like ATF2 and c-Jun.
  • The specific genes mediating JNK-driven cellular responses, particularly DNA repair, remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the genes and mechanisms involved in JNK-mediated DNA repair following genotoxic stress.
  • To investigate the role of ATF2 and c-Jun phosphorylation in regulating gene expression during the DNA damage response.

Main Methods:

  • Utilized chromatin immunoprecipitation (ChIP) with specific antibodies against ATF2, c-Jun, and their phosphorylated forms.
  • Employed promoter arrays to identify genes bound by ATF2 and c-Jun following cisplatin treatment.
  • Validated findings using transplatin, a JNK inhibitor (SP600125), and JNK-specific siRNA.

Main Results:

  • Identified 269 genes whose promoters are bound by phosphorylated ATF2 and c-Jun following genotoxic stress.
  • Demonstrated that this binding is dependent on JNK activity, as it was blocked by transplatin, SP600125, and JNK siRNA.
  • Found that 23 out of 89 known DNA repair genes were specifically activated by cisplatin within 3-6 hours.

Conclusions:

  • The genotoxic stress response, particularly DNA repair, is significantly mediated by the activation of ATF2 and c-Jun.
  • Cisplatin treatment triggers a large-scale, coordinated gene expression program dominated by DNA repair genes via JNK signaling.
  • This study clarifies a key pathway in cellular response to DNA damage, highlighting the role of JNK-AP-1 signaling in coordinating DNA repair gene activation.

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