Upstream and downstream signals of Ubc9 sumoylation

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The small ubiquitin related modifier SUMO regulates protein function in a covalent and non-covalent manner. Deregulation of the SUMO pathway is implicated in the pathogenesis of diseases like cancer or diverse neurodegenerative disorders. Sumoylation (covalent SUMO attachment to the substrate) is controlled by an energy dependent enzyme cascade for conjugation and by a set of enzymes for de-conjugation. My laboratory is interested in understanding the regulation at the level of SUMO conjugation, which is catalysed by one E1 activating enzyme, one E2 conjugating enzyme and one of a few E3 ligases. To date, hundreds of SUMO substrates are identified but it is unclear how substrate specificity is performed with this limited number of enzymes. Although sumoylation is mainly modulated via E3 ligases, our recent findings indicate that the E2 enzyme Ubc9 contributes to regulate target discrimination. We have shown that Ubc9 itself gets sumoylated resulting in a switch in target discrimination. Biochemical and structural analysis indicate that this modification enhances sumoylation of the transcriptional regulator Sp100 to an extent that can otherwise only be achieved in the presence of E3 ligases whereas other substrates are not altered or even impaired. The overall aim of this proposal is to characterise regulation and the consequences of this particular Ubc9 modification in a biological context.