Ubiquitin Pathway

Abstract Ubiquitination is an enzymatic process that involves the covalent attachment of the conserved protein ubiquitin to a substrate. Protein ubiquitination is carried out by the sequential and coordinate actions of three enzymes and can be removed by deubiquitinases. Modification of proteins by addition of ubiquitin exerts both proteolytic‐dependent and proteolytic‐independent functions. Polyubiquitin chains act as a signal for 26S proteasome‐mediated degradation. Ubiquitination plays a central regulatory role in a number of cellular processes such as receptor endocytosis, cell cycle control, transcription, DNA repair, gene silencing and stress response. The ubiquitin proteasome system (UPS) is critical for the proper turnover of both oncoproteins and tumour suppressor molecules. As a result, it is not surprising that aberrations within the UPS often result in a neoplastic phenotype. Key Concepts Ubiquitination is an ATP‐dependent and reversible process through which ubiquitin is covalently attached to a polypeptide. The topology of the polyubiquitin chains dictates the fate of the modified protein. Deubiquitinating enzymes (DUBs) are proteases that reversely modify proteins by removing ubiquitin. The RING finger type E3 ligases crucially control cell cycle entry and progression. The proteasome is a proteolytic ‘machinery’ that digests proteins into short polypeptides. The ubiquitin proteasome system (UPS) degrades 80–90% of all intracellular proteins. The UPS regulates the timing and extent of protein turnover.