The Ubiquitin-Proteasome System (UPS) is an important regulator of cell signaling and proteostasis, which are essential to a variety of cellular processes. The UPS is disrupted in many diseases including cancer, and targeting the UPS for cancer therapy is gaining wide interest. E3 ubiquitin ligases occupy a key position in the hierarchical UPS enzymatic cascade, largely responsible for determining substrate specificity and ubiquitin (Ub) chain topology. The E3 ligase UBR5 (aka EDD1) is emerging as a key regulator of the UPS in cancer and development. UBR5 expression is deregulated in many cancer types and UBR5 is frequently mutated in mantle cell lymphoma. UBR5 is highly conserved in metazoans, has unique structural features, and has been implicated in regulation of DNA damage response, metabolism, transcription, and apoptosis. Hence, UBR5 is a key regulator of cell signaling relevant to broad areas of cancer biology. However, the mechanism by which UBR5 may contribute to tumor initiation and progression remains poorly defined. This review synthesizes emerging insights from genetics, biochemistry, and cell biology to inform our understanding of UBR5 in cancer. These molecular insights indicate a role for UBR5 in integrating/coordinating various cellular signaling pathways. Finally, we discuss outstanding questions in UBR5 biology and highlight the need to systematically characterize substrates, and address limitations in current animal models, to better define the role of UBR5 in cancer.

Protein ubiquitylation is a widespread post-translational modification, regulating cellular signalling with many outcomes, such as protein degradation, endocytosis, cell cycle progression, DNA repair and transcription. E3 ligases are a critical component of the ubiquitin proteasome system (UPS), determining the substrate specificity of the cascade by the covalent attachment of ubiquitin to substrate proteins. Currently, there are over 600 putative E3 ligases, but many are poorly characterized, particularly with respect to individual protein substrates. Here, we highlight systematic approaches to identify and validate UPS targets and discuss how they are underpinning rapid advances in our understanding of the biochemistry and biology of the UPS. The integration of novel tools, model systems and methods for target identification is driving significant interest in drug development, targeting various aspects of UPS function and advancing the understanding of a diverse range of disease processes.