Drosophila melanogaster MNK/Chk2 and p53 regulate multiple DNA repair and apoptotic pathways following DNA damage

Mol Cell Biol. 2004 Feb;24(3):1219-31. doi: 10.1128/mcb.24.3.1219-1231.2004.

Abstract

We have used genetic and microarray analysis to determine how ionizing radiation (IR) induces p53-dependent transcription and apoptosis in Drosophila melanogaster. IR induces MNK/Chk2-dependent phosphorylation of p53 without changing p53 protein levels, indicating that p53 activity can be regulated without an Mdm2-like activity. In a genome-wide analysis of IR-induced transcription in wild-type and mutant embryos, all IR-induced increases in transcript levels required both p53 and the Drosophila Chk2 homolog MNK. Proapoptotic targets of p53 include hid, reaper, sickle, and the tumor necrosis factor family member EIGER: Overexpression of Eiger is sufficient to induce apoptosis, but mutations in Eiger do not block IR-induced apoptosis. Animals heterozygous for deletions that span the reaper, sickle, and hid genes exhibited reduced IR-dependent apoptosis, indicating that this gene complex is haploinsufficient for induction of apoptosis. Among the genes in this region, hid plays a central, dosage-sensitive role in IR-induced apoptosis. p53 and MNK/Chk2 also regulate DNA repair genes, including two components of the nonhomologous end-joining repair pathway, Ku70 and Ku80. Our results indicate that MNK/Chk2-dependent modification of Drosophila p53 activates a global transcriptional response to DNA damage that induces error-prone DNA repair as well as intrinsic and extrinsic apoptosis pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • Checkpoint Kinase 2
  • DNA Damage / physiology*
  • DNA Repair / physiology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila Proteins / radiation effects
  • Drosophila melanogaster / metabolism
  • Drosophila melanogaster / radiation effects
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Proteins / radiation effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / radiation effects
  • Radiation, Ionizing
  • Transcription, Genetic / radiation effects
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Protein p53 / radiation effects

Substances

  • Drosophila Proteins
  • Membrane Proteins
  • Tumor Suppressor Protein p53
  • egr protein, Drosophila
  • Checkpoint Kinase 2
  • Protein-Serine-Threonine Kinases
  • lok protein, Drosophila