E3 ubiquitin-protein ligase UBR5 (UBR5)

E3 ubiquitin-protein ligase UBR5 is a large, multidomain nuclear enzyme (~309 kDa) that belongs to the HECT (Homology to E6AP C-Terminus) family of E3 ubiquitin ligases. UBR5 catalyzes the transfer of ubiquitin to substrate proteins, marking them for degradation via the proteasome. It contains an N-terminal region with protein-protein interaction domains, central armadillo (ARM) repeats, and a C-terminal HECT domain that mediates its catalytic activity[1][5][7]. UBR5 further contains a UBR-box for recognition of substrate N-degrons, a ubiquitin association (UBA) domain, small β-barrel domains (SBBs), and an MLLE domain important for protein interactions[1]. The enzyme is able to oligomerize (dimer and tetramer forms), which influences substrate engagement and its catalytic mechanisms[1][5][7]. UBR5 plays major roles in regulating the cell cycle by ubiquitinating mitotic checkpoint proteins such as Bub3, BubR1, and Cdc20. It influences assembly/disassembly of the mitotic checkpoint complex (MCC), impacting cell division and genomic stability[4]. Beyond cell cycle control, UBR5 is critical for embryonic development and is involved in apoptosis, protein quality control, DNA damage response, immune regulation, and miRNA-mediated gene silencing[2][5]. Dysregulation or overexpression of UBR5 is associated with cancer initiation and progression, metastasis, chemoresistance, especially resistance to gemcitabine in pancreatic cancer, and possibly other pathologies[6]. Because of its role in cancer and other cellular processes, UBR5 is considered a promising therapeutic target, especially in oncology. Several efforts, including structure-based drug development, are ongoing to develop direct UBR5 inhibitors, with Y-39983 dihydrochloride identified as a candidate that sensitizes cancer cells to chemotherapy[6]. UBR5's broad substrate range and its effects on key cellular pathways mean that therapeutic targeting may require careful safety assessments to minimize undesired effects on cell proliferation and viability.

Other names

EDDEDD1HYDhHYDDD5KIAA0896HECT domain-containing 1Hyperplastic discs protein homologProgestin-induced proteinE3 identified by differential display

Inhibition of UBR5's E3 ligase activity (leading to reduced ubiquitination and degradation of substrates; chemosensitization in cancer therapy)