An<i>in vivo</i>genetic screen in<i>Drosophila</i>identifies the orthologue of human cancer/testis gene<i>SPO11</i>among a network of targets to inhibit<i>lethal(3)malignant brain tumour</i>growth

Abstract

Using transgenic RNAi technology, we have screened over 4000 genes to identify targets to inhibit malignant growth caused by the loss of function of <i>lethal(3)malignant brain tumour</i> in <i>Drosophila in vivo</i> We have identified 131 targets, which belong to a wide range of gene ontologies. Most of these target genes are not significantly overexpressed in mbt tumours hence showing that, rather counterintuitively, tumour-linked overexpression is not a good predictor of functional requirement. Moreover, we have found that most of the genes upregulated in mbt tumours remain overexpressed in tumour-suppressed double-mutant conditions, hence revealing that most of the tumour transcriptome signature is not necessarily correlated with malignant growth. One of the identified target genes is <i>meiotic W68</i> (<i>mei-W68</i>), the <i>Drosophila</i> orthologue of the human cancer/testis gene <i>Sporulation-specific protein 11</i> (<i>SPO11</i>), the enzyme that catalyses the formation of meiotic double-strand breaks. We show that <i>Drosophila mei-W68/SPO11</i> drives oncogenesis by causing DNA damage in a somatic tissue, hence providing the first instance in which a <i>SPO11</i> orthologue is unequivocally shown to have a pro-tumoural role. Altogether, the results from this screen point to the possibility of investigating the function of human cancer relevant genes in a tractable experimental model organism like <i>Drosophila.</i>