Ubiquitin And SUMO Post-Translational Modifications In Development And Disease

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Post-translational modification with the ubiquitin-like SUMO proteins regulates a wide range of cellular processes. Our work on the desumoylating enzyme SENP1 was the first to show a role for this pathway in development, specifically in the formation and function of the placenta. A major question in the SUMO field is how is specificity achieved. How are specific target proteins selected for sumoylation or desumoylation and what specifies the conjugation of SUMO1 vs. SUMO2 or SUMO3? We have shown that mice lacking SUMO1 are viable, apparently due to the compensatory utilization of SUMO2/3 for sumoylation of SUMO1 targets. Additional insight into the distinct and shared functions of the different SUMO proteins has come from further analysis of the SENP1 mutant. Our previous data suggested that the observed SENP1 phenotypic defects were due specifically to higher steady state levels of conjugated SUMO1 only, and not SUMO2 or SUMO3. We therefore asked whether reducing total SUMO1 levels in the SENP1 mutant background would rescue the phenotype. We had noted that mice heterozygous for the SUMO1 mutation showed a significant reduction in the level of high molecular mass SUMO1 conjugates. By crossing to the SENP1 mutant we generated SENP1 homozygous embryos that were also heterozygous for the SUMO1 mutation. These were found to have a striking reduction in the level of SUMO1 conjugates, approaching wild-type levels, although desumoylation activity still is compromised in these embryos. Importantly, these embryos survived to birth providing firm evidence that the SENP1 developmental defects are SUMO1 dependent. Surprisingly, completely eliminating SUMO1 from the SENP1 mutant background causes a more severe phenotype, with mutants dying at even earlier developmental stages. Unlike SUMO1 or SENP1 mutants, the double homozygous embryos accumulate significant levels of SUMO2/3 conjugated proteins. These findings provide further evidence that target proteins normally sumoylated with SUMO1 can undergo compensatory conjugation with SUMO2/3 upon the loss of SUMO1. Further, in the additional absence of SENP1, the accumulation of these SUMO2/3 conjugates can have even more severe consequences for the developing embryo perhaps because of inappropriate SUMO paralog usage.