title: Degrons in cancer.
abstract: 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.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 2 Magyar Tudósok krt, Budapest H-1117, Hungary.
authors.forename: Bálint
authors.identifier: http://orcid.org/0000-0003-0919-4449
authors.initials: B
authors.lastname: Mészáros
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Manjeet
authors.identifier: http://orcid.org/0000-0002-3004-2151
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany. dosztanyi@caesar.elte.hu.
authors.forename: Toby J
authors.identifier: http://orcid.org/0000-0003-0657-5166
authors.initials: TJ
authors.lastname: Gibson
authors.affiliation: Bioinformatics Platform, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Bora
authors.identifier: http://orcid.org/0000-0002-3170-4890
authors.initials: B
authors.lastname: Uyar
authors.affiliation: MTA-ELTE Lendület Bioinformatics Research Group, Department of Biochemistry, Eötvös Loránd University, Pázmány Péter stny 1/c, Budapest H-1117, Hungary. dosztanyi@caesar.elte.hu.
authors.forename: Zsuzsanna
authors.identifier: http://orcid.org/0000-0002-3624-5937
authors.initials: Z
authors.lastname: Dosztányi
mesh_terms: D001665:Binding Sites / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000072417:Protein Domains; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease