Originally published as Genetics Published Articles Ahead of Print on April 13, 2009.

Genetics, Vol. 182, 423-435, June 2009, Copyright © 2009
doi:10.1534/genetics.109.102327

p53-Independent Apoptosis Limits DNA Damage-Induced Aneuploidy

Laura M. McNamee and Michael H. Brodsky1

Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605

1 Corresponding author: 623 Lazare Research Bldg., Program in Gene Function and Expression, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605.
E-mail: michael.brodsky{at}umassmed.edu

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.