p53-independent apoptosis limits DNA damage-induced aneuploidy.
DNA damage or unprotected telomeres can trigger apoptosis via signaling pathways that directly sense abnormal DNA structures and activate the p53 transcription factor. We describe a p53-independent mechanism that acts in parallel to the canonical DNA damage response pathway in Drosophila to induce apoptosis after exposure to ionizing radiation. Following recovery from damage-induced cell cycle arrest, p53 mutant cells activate the JNK pathway and expression of the pro-apoptotic gene hid. Mutations in grp, a cell cycle checkpoint gene, and puc, a negative regulator of the JNK pathway, sensitize p53 mutant cells to ionizing radiation (IR)-induced apoptosis. Induction of chromosome aberrations by DNA damage generates cells with segmental aneuploidy and heterozygous for mutations in ribosomal protein genes. p53-independent apoptosis limits the formation of these aneuploid cells following DNA damage. We propose that reduced copy number of haploinsufficient genes following chromosome damage activates apoptosis and helps maintain genomic integrity.
McNamee
Laura M
LM
University of Massachusetts Medical School, Worcester, MA 01605, USA.
Brodsky
Michael H
MH
D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D020169:Caspases / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000528:radiation effects; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000528:radiation effects; D009479:Neuropeptides / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D011839:Radiation, Ionizing; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D029721:Drosophila Proteins; C108880:HID protein, Drosophila; D009479:Neuropeptides; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C118082:brk protein, Drosophila; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605877:grp protein, Drosophila; D048670:MAP Kinase Kinase 4; C110854:puc protein, Drosophila; D010749:Phosphoprotein Phosphatases; D020169:Caspases