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Ubiquitin-like proteins (Ubls) are conjugated to target proteins or lipids to regulate their activity, stability, subcellular localization, or macromolecular interactions. Conjugation is achieved through a cascade of activities that are catalyzed by E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. We are focused on understanding how Ubl conjugation pathways achieve selectivity for particular targets, and how conjugation generates signals in processes ranging from DNA repair to the cell cycle.