A forward genetic approach to mapping a P-element second site mutation identifies DCP2 as a novel tumor suppressor in Drosophila melanogaster

Abstract

The use of transposons to create mutants has been the cornerstone of Drosophila genetics in the past few decades. Transpositions often create second-site mutations, devoid of transposon insertion and thereby affect subsequent phenotype analyses. In a P-element mutagenesis screen, a second site mutant was discovered on chromosome 3 wherein the homozygous mutant individuals show the classic hallmarks of mutations in tumor suppressor genes including brain tumour and lethality, hence the mutant line was initially named as lethal (3) tumorous brain [l(3)tb]. Classical genetic approaches relying on meiotic recombination and subsequent complementation with chromosomal deletions and gene mutations mapped the mutation to CG6169, the mRNA decapping protein 2 (DCP2), on the left arm of the third chromosome (3L), and thus the mutation was renamed as DCP2l(3)tb. Fine mapping of the mutation further identified the presence of a Gypsy-LTR like sequence in the 5UTR coding region of DCP2, alongwith expansion of the adjacent upstream intergenic AT-rich sequence. The mutant phenotypes are rescued by Introduction of a functional copy of DCP2 in the mutant background, thereby establishing the causal role of the mutation and providing a genetic validation of the allelism. With the increasing repertoire of genes being associated with tumor biology this is the first instance that the mRNA decapping protein is being implicated in Drosophila tumourigenesis. Our findings therefore imply a plausible role for mRNA degradation pathway in tumorigenesis and identify DCP2 as a potential candidate for future explorations of cell cycle regulatory mechanisms.