Drosophila melanogaster MNK/Chk2 and p53 regulate multiple DNA repair and apoptotic pathways following DNA damage.
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.
Brodsky
Michael H
MH
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. michael.brodsky@umassmed.edu
Weinert
Brian T
BT
Tsang
Garson
G
Rong
Yikang S
YS
McGinnis
Nadine M
NM
Golic
Kent G
KG
Rio
Donald C
DC
Rubin
Gerald M
GM
D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D004331:Drosophila melanogaster / Q000378:metabolism / Q000528:radiation effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000528:radiation effects; D011839:Radiation, Ionizing; D014158:Transcription, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000528:radiation effects
D029721:Drosophila Proteins; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; C464573:egr protein, Drosophila; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; C112435:lok protein, Drosophila