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There are many cellular proteins that need to be eliminated quickly in response to changing conditions in or around the cells. Most of these proteins carry a short functional element in their sequence, called a degron. Degrons are typically composed of 6 to 10 amino acids and are generally located within flexible regions of proteins so that the degrons can easily interact with other proteins. E3 ubiquitin ligases bind to specific degrons, enabling the attachment of multiple copies of ubiquitin to target proteins. The ubiquitin chains are a molecular signal that directs the proteins to the proteasome, where the tagged proteins are chopped up into pieces and recycled. The correct removal of proteins is important for many biological processes, such as regulating transcription and controlling the major steps during cell division. Regulated protein degradation also turns off the activity of some proteins that are activated by transient external signals. The encounter between the E3 ligase and the degron determines whether a protein lives or dies. There are ~600 different E3 ligases that are encoded in the human genome. Each of these E3 ligases targets a different set of proteins and operates under a different condition. This ubiquitin-mediated protein degradation process is regulated at multiple levels. Defects in this system can cause systemic diseases, including cancer. This Review with 8 figures, 1 table, and 360 references describes how mutations that affect ubiquitin-mediated protein degradation system contribute to cancer.
Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes ~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Loss-of-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the β-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the “dark degrome” (unknown degron-E3 relationships) would enhance progress in cancer research.