SUMOGROUP · Principles of Protein Group Modification by the SUMO Pathway

Posttranslational modification (PTM) of proteins by ubiquitin family proteins is of fundamental importance for cellular function, regulation and development. Ubiquitylation typically targets individual proteins, and high selectivity is achieved by a plethora of ubiquitin-conjugating enzymes and ligases. Much less is known regarding how modification by the ubiquitin-related protein SUMO influences the function of substrates and how specificity is provided. Surprisingly, although SUMOylation affects roughly 10% of all yeast proteins, only very few enzymes participate in the pathway. Moreover, although SUMOylation is essential for viability, mutants defective in SUMOylation of individual substrates usually lack deleterious phenotypes. We recently solved this puzzle as we found that SUMOylation frequently targets protein groups (“protein group modification”) rather than individual substrates; single modifications are often redundant or additive as SUMO functions as intermolecular “glue”, thereby stabilizing protein complexes. Hence, the traditional view that a single PTM on a given protein mediates a specific function does not seem to apply for many SUMO modifications.Entirely divergent from previous approaches we will thus focus for the first time specifically on protein group SUMOylation and its special requirements for specificity, induction and termination. Initially found for proteins of homologous recombination and nucleotide excision DNA repair, we will expand the concept of protein group SUMOylation with a focus on pathways relevant for cellular regulation and which are of medical importance. We will define the substrate repertoire of SUMO ligases, characterize their substrate targeting properties, and design novel tools aimed to address the function of protein group SUMOylation. We expect that our work will finally put studies of this important modifier on a solid basis and will break new ground in areas of cellular regulation and cell biology in general.