The Evolution and Functional Diversification of the Deubiquitinating Enzyme Superfamily

Abstract

Ubiquitin and ubiquitin-like molecules are attached to and removed from cellular proteins in a dynamic and highly regulated manner. Deubiquitinating enzymes are critical to this process, and the genetic catalogue of deubiquitinating enzymes expanded greatly over the course of evolution. Extensive functional redundancy has been noted among the 93 members of the human deubiquitinating enzyme (DUB) superfamily. This is especially true of genes that were generated by duplication (termed paralogs) as they often retain considerable sequence similarity. Because complete redundancy in systems should be eliminated by selective pressure, we theorized that many overlapping DUBs must have significant and unique spatiotemporal roles that can be evaluated in an evolutionary context. We have determined the evolutionary history of the entire class of deubiquitinating enzymes, including the sequence and means of duplication for all paralogous pairs. To establish their uniqueness, we have investigated cell-type specificity in developmental and adult contexts, and have investigated the coemergence of substrates from the same duplication events. Our analysis has revealed examples of DUB gene subfunctionalization, neofunctionalization, and nonfunctionalization.

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

“…1E and G, Table S3). We and others found that USP15 (Baker et al, 1999) is expressed in the early progenitor compartment (LSK) and in HSC (Cabezas-Wallscheid et al, 2014;Lancini et al, 2016), as well as in blood and in splenic B cells (Lancini et al, 2016;Vlasschaert et al, 2017). Together with our screen results, these data suggest a potential role for USP15 in hematopoiesis, though no functional study in vivo has yet been reported.…”

Deubiquitinating Enzymes in Model Systems and Therapy: Redundancy and Compensation Have Implications

“…The ancestral vertebrate genome appears to have encoded 61 DUBS, and the expanded repertoire of modern vertebrates is largely the product of two rounds of whole genome duplication (referred to as 2R‐WGD) dating to the Cambrian period roughly 500 million years ago; a smaller number arose from small segmental duplications or retrotransposition events. Most duplicated genes are silenced as the result of negative selection or genetic drift, and their pseudogenization or ultimate loss is consistent with the absence of the even greater abundance of DUBs predicted to have been generated by 2R‐WGD . The remaining duplicates can have a high degree of sequence similarity, particularly those arising from WGD (designated ohnologues in recognition of Susumu Ohno who explained the prevalence and origin of such duplicates).…”

“…The activities of enzymes promoting or opposing the assembly of chains are in many cases regulated by post‐translational modifications of the enzymes (notably by phosphorylation events), allowing the dynamic fine‐tuning of ubiquitin‐mediated processes in response to changes in cellular milieu. The genomes of metazoan organisms encode in the order of 100 DUBs and we have recently provided an evolutionary account of their origins . For the analysis that follows, we chose to concentrate on the state of affairs in vertebrate DUBs—in particular on the ubiquitin‐specific proteases (which comprise the largest family of DUBs in vertebrates).…”

“…Although we have focused our discussion on the ohnologue pair of USP4 and USP15, similar arguments could be made for other USP ohnologue pairs. To cite one further example, USP5 and USP13 also arose from whole genome duplication and have become subfunctionalized through expression in specific layers of tissue such as the retina . Morpholino experiments in zebrafish reveal a profound developmental defect when USP5 is targeted, although the effects of USP5 RNA depletion are more subtle in cultured human cells treated with siRNA …”

“…In the nonsense‐induced transcriptional compensation (NITC) response, the fragments generated by mRNA degradation are directed to the nucleus where they bind to complementary DNA sequences of highly related genes, promoting their epigenetic reprogramming and ultimate transcriptional activation to levels sufficient for rescue. It remains to be seen whether the NITC response is operative in inactivating mutations involving DUBs, but the prevalence of ohnologues in the USP genes in particular makes this subset the logical place to look. As a starting point, we have therefore completed a systematic examination of the literature mentioning inactivating mutations of USP genes in genetically modified strains of mice (summarized in Table , which updates and expands upon a previously published inventory of mutations and their phenotypes).…”