Ubiquitination—the covalent conjugation of ubiquitin (Ub) to other cellular proteins—regulates a wide range of cellular processes. Often, multiple Ub molecules are added to the substrate to form a Ub chain. Distinct outcomes have been observed for substrates modified with multi-Ub chains linked through particular lysine residues. However, recent studies suggest that Ub chain linkages may not be the key determinant for substrate fate. Here, we review evidence suggesting that Ub-bindin
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