Deciphering the Functional Redundancy of USP4 and USP15

Abstract

The deubiquitinating enzymes USP4 and USP15 are encoded by genes that are ohnologues arising from whole genome duplication events early in vertebrate evolution, and the majority of known vertebrate genomes contain a functional copy of both. Both USPs are known to be involved in some of the same signalling pathways such as Wnt/β-catenin, however subfunctionalization has occurred such that they each regulate the stability of distinct substrates. Despite their sequence and evolutionary similarities, the ohnologues may have opposite correlations in overall survival of lung adenocarcinoma patients. Early work with knockout mice has determined that while mice null in one ohnologue display no phenotype, the double null genotype is lethal. We hypothesize that there are mechanisms in place that allow one to perform the other’s functions to a certain extent when deficient in one USP. To study the extent of this functional redundancy, we are analyzing the progeny of genetic crosses of mice in which one or both genes have been inactivated. There is evidence for partial functional redundancy and more severe phenotypes when deficient in USP15. Embryos null for both genes die at midgestation and are physically smaller than embryos heterozygous for both genes. They have underdeveloped livers, and a likely defect in hematopoiesis. Proper fetal hematopoiesis requires signalling through Wnt/ β-catenin pathway, and a systematic analysis of the components of this pathway has been undertaken to correlate deficiencies with the genotypes of our knockout mice. There also may be preliminary evidence of transcriptional compensation in one ohnologue USP when the related USP is knocked out. These findings will have implications for potential targeted therapies.