Ubiquitin (Ub) and ubiquitin-like (Ubl) proteins including small Ubl modifier (SUMO) are small proteins which are covalently linked to target proteins to regulate their functions. In this review, we discuss the current state of the art and point out what we feel this field urgently needs in order to delineate the wiring of the system. We discuss what is needed to unravel the connections between different components of the conjugation machineries for ubiquitylation and SUMOylation, and to unravel the connections between the conjugation machineries and their substrates. Chemical probes are key tools to probe signal transduction by these small proteins that may help understand their action. This rapidly moving field has resulted in various small molecules that will help us to further understand Ub and SUMO function and that may lead to the development of new drugs.

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