Expanding SUMO and ubiquitin-mediated signaling through hybrid SUMO-ubiquitin chains and their receptors

Monomeric and polymeric forms of SUMO and ubiquitin are covalently attached to substrates and recognized by effector proteins containing SUMOinteracting motifs (SIMs) or ubiquitininteracting motifs (UIMs), thereby triggering a wide range of biological responses. SUMO and ubiquitin were thought to represent distinct homotypic signals, until recent studies revealed the presence of hybrid SUMO-Ub chains. Synthesis of SUMO-Ub chains is dependent on the activity of SUMO-targeted ubiquitin ligases (STUbLs) that specifically recognize and ubiquitinate SUMO chains on substrates (Fig. 1A). SUMO-Ub chains were originally identified on proteins destined for proteasomal degradation. As exemplified in humans, SUMO-Ub chains synthesized by RNF4 target PML (promyelocytic leukemia protein) for proteasomal degradation. However, it remained unclear whether SUMO-Ub chains are recognized as distinct signals by hybrid chain-specific receptors or by receptors recognizing ubiquitin alone. Recently, we provided two important insights into SUMO-Ub chain signaling. We revealed that hybrid chains are recognized as distinct entities by receptor proteins containing tandem SUMOand ubiquitin-interacting motifs (tSIM-UIMs), and that hybrid chains mediate recruitment of DNA repair factors to damage sites. RAP80, a subunit of the BRCA1-A complex, contains tandem UIMs that mediate high affinity interactions with K63-linked ubiquitin chains formed at DNA damage sites. We characterized RAP80 as the first SUMO-Ub Expanding SUMO and ubiquitin-mediated signaling through hybrid SUMO-ubiquitin chains and their receptors