SUMO in the DNA damage response

Post-translational modification by Small Ubiquitinlike Modifiers (SUMOs) is critical for all eukaryotic life [1]. SUMO, like ubiquitin, is conjugated to lysine residues in target proteins through an enzymatic cascade involving E1, E2 and E3 enzymes, and SUMOylation of proteins can be reversed through the action of SUMO-specific proteases. SUMO is generally known as a modifier of transcription and is a key player in the DNA damage response (DDR), with various DNA repair factors being SUMOylated in response to DNA damage, and an overall increased presence of SUMOylation at sites of DNA damage [2]. SUMO non-covalently interacts with other proteins through SUMO interaction motifs (SIMs). A well-known protein containing SIMs is the E3 ubiquitin ligase RNF4, which functions as a SUMO-targeted ubiquitin ligase. RNF4 generally ubiquitylates polySUMOylated proteins in order to facilitate their degradation, and performs an important role in the DDR [3]. Through multiple interactions between SUMOs and SIMs within different subunits of protein complexes, SUMO/SIM interactions are believed to serve as a mechanism to stabilize macromolecular structures [4]. Recently, major advances in proteomics have led to a more in-depth characterization of the SUMOylated proteome, uncovering over a thousand SUMO substrates and many thousands of SUMOylated lysines [5, 6]. These results have further underlined the important roles of SUMOs in all nuclear processes, revealing large numbers of transcriptional regulators, chromatin modifiers, and DDR factors as SUMO target proteins. Whereas transcription factors and DDR factors are major groups of SUMO target proteins, little was known about how SUMO coordinates transcriptional regulation in response to DNA damage. We recently investigated the involvement of SUMO in the DDR at a proteome wide level, using the latest proteomics methods and tools available to quantitatively study changes in protein SUMOylation in response to cellular treatment with the DNA damaging agent methyl methanesulfonate (MMS) [7]. Through usage of an unbiased and system-wide approach, we identified subsets of 20 and 33 proteins being upregulated and downregulated in SUMOylation, respectively, in response to DNA damage. Furthermore, we quantitatively mapped 755 SUMOylation sites of which 362 were dynamic in response to MMS. Strikingly, we observed a cluster of chromatin modifiers, transcription factors and DNA repair factors to be differentially SUMOylated, providing new insight in how SUMO Editorial