E2F1 promotes, JNK and DIAP1 inhibit, and chromosomal position has little effect on radiation-induced Loss of Heterozygosity inDrosophila

Abstract

Loss of Heterozygosity (LOH) can occur when a heterozygous mutant cell loses the remaining wild type allele to become a homozygous mutant. LOH can have physiological consequences if, for example, the affected gene encodes a tumor suppressor. We used two fluorescent reporters to study mechanisms of LOH induction by X-rays, a type of ionizing radiation (IR), in Drosophila larval wing discs. IR is used to treat more than half of cancer patients, so understanding its effects is of biomedical relevance. We report that IR-induced LOH does not correlate with the chromosomal position of the LOH locus, unlike previously shown for spontaneously occurring LOH. Like spontaneous LOH, however, IR-induced LOH of X-linked loci shows a sex-dependence, occurring predominately in females. A focused genetic screen identified E2F1 as a key promotor of LOH and further testing suggests a mechanism involving its role in cell cycle regulation rather than apoptosis. We combined the QF/QS LOH reporter with QUAS-transgenes to manipulate gene function after LOH induction. This approach identified JNK signaling and apoptosis as key determinants of LOH maintenance. These studies reveal previously unknown mechanisms for generation and maintenance of cells with chromosome aberrations after exposure to IR.