A key regulator of DNA damage-induced apoptosis is the tumor suppressor gene, p53. p53 is a transcription factor that upregulates genes involved in cell cycle arrest, apoptosis, and senescence. How p53 decides to activate one of these responses in response to DNA damage is largely unanswered. Many have hypothesized it is due to interaction with various signaling pathways and post-translational modification. The p53 tumor suppressor can be modified by SUMO-1 in mammalian cells, but the functional consequences of this modification are unclear. Conjugation to SUMO is a reversible post-translational modification that regulates several transcription factors involved in cell proliferation, differentiation, and disease. In Chapter II, we demonstrate that the Drosophila homolog of human p53 can be efficiently sumoylated in insect cells. We identify two lysine residues involved in SUMO attachment, one at the C-terminus, between the DNA binding and oligomerization domains, and one at the N-terminus of the protein. We find that sumoylation helps recruit Drosophila p53 to nuclear dot-like structures that can be marked by human PML and the Drosophila homologue of Daxx. We demonstrate that mutation of both sumoylation sites dramatically reduces the transcriptional activity of p53 and its ability to induce apoptosis in transgenic flies, providing in vivo evidence that sumoylation is critical for Drosophilap53 function. Many therapeutic cancer treatments rely on DNA-damaging agents to induce apoptosis in cancer cells. However, fifty percent of all human tumors lack functional p53 and p53 mutant cells are partially resistant to damage-induced apoptosis. Therefore, it is important to identify mechanisms to induce apoptosis independent of p53. Drosophila provides a good model system to study p53-independent apoptosis because it contains a single p53 homolog. In Chapter III, we describe a p53-independent mechanism that acts in parallel to the canonical DNA damage response pathway in Drosophila to activate apoptosis in response to inappropriately repaired chromosome breaks. Induction of chromosome aberrations by DNA damage followed by cell division results in segmental aneuploidy and reduced copy number of ribosomal protein genes. We find that activation of the pro-apoptotic gene hid by the JNK pathway acts in a p53-independent mechanism to induce apoptosis and limit the formation of aneuploid cells. Mutations in grp, the Drosophila Chk1 homolog, and puc, a negative regulator of the JNK pathway sensitize p53 mutant cells to IR-induced apoptosis. We propose a model in which the death of cells with reduced copy number of genes required for cell survival helps maintain genomic integrity following chromosome damage