A Chain of Events: Regulating Target Proteins by SUMO Polymers

Highlights

• STUbLs recognize the composition of SUMO chains as demonstrated by the preference of RNF4 for homogeneous SUMO-2 chains while RNF111 has a preference for SUMO-1-capped chains.

• Depletion of the polySUMO protease SENP6 leads to a broad range of cellular defects including reduced accumulation at the centromere of most members of the constitutive centromere-associated network, improper spindle assembly, and micronuclei, thereby impairing proper cell cycle progression.

• In mammals, SENP6 and SENP7 are responsible for the cleavage of polymeric SUMO. These two proteases are expected to have distinctive pools of target proteins since they cannot compensate for each other.

• Inhibitors targeting the SUMOylation machinery, either by blocking conjugation or by blocking deconjugating enzymes, could be promising anticancer therapies.

Small ubiquitin-like modifiers (SUMOs) regulate virtually all nuclear processes. The fate of the target protein is determined by the architecture of the attached SUMO protein, which can be of polymeric nature. Here, we highlight the multifunctional aspects of dynamic signal transduction by SUMO polymers. The SUMO-targeted ubiquitin ligases (STUbLs) RING-finger protein 4 (RNF4) and RNF111 recognize SUMO polymers in a chain-architecture-dependent manner, leading to the formation of hybrid chains, which could enable proteasomal destruction of proteins. Recent publications have highlighted essential roles for SUMO chain disassembly by the mammalian SUMO proteases SENP6 and SENP7 and the yeast SUMO protease Ulp2. SENP6 is particularly important for centromere assembly. These recent findings demonstrate the diversity of SUMO polymer signal transduction for proteolytic and nonproteolytic purposes.