{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBE2O functions as an atypical ubiquitin‐conjugating enzyme that directly modifies nuclear proteins to control their localization and signaling. For instance, it multi‐monoubiquitinates the nuclear localization signal of the tumor suppressor BAP1, forcing its cytoplasmic sequestration and consequently affecting chromatin regulation and cell differentiation, while also modifying SMAD6 to modulate BMP signaling and dampen its inhibitory activity, and by binding TRAF6 to inhibit its K63‐polyubiquitination and downstream NF‑κB activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of tumorigenesis and metabolic reprogramming, UBE2O emerges as a key oncogenic driver. It targets crucial metabolic regulators such as AMPKα for ubiquitination and proteasomal degradation, thereby promoting activation of the mTOR‑HIF1α pathway and fostering tumor initiation, growth, metastasis, and even radioresistance in cancers including lung, breast, and hepatocellular carcinoma. This activity extends to the regulation of oncoproteins like MYC and the control of differentiation processes, as seen by its impact on Mxi1 stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in signaling and cancer, UBE2O acts as a self‐contained quality control factor. It directly recognizes exposed hydrophobic and basic patches on orphan proteins—such as unassembled α‑globin or ribosomal proteins—and catalyzes their multi‐mono ubiquitination to flag them for degradation, thereby maintaining protein homeostasis. Additionally, it mediates the ubiquitination of RECQL4, attenuating its interaction with key double‑strand break repair proteins and influencing homologous recombination."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies have broadened the functional repertoire of UBE2O. It regulates circadian rhythms by ubiquitinating and destabilizing BMAL1, thereby modulating its transcriptional activity, and it is hijacked by the HIV‑1 Tat protein to ubiquitinate HEXIM1—resulting in the release of P‑TEFb and enhanced transcriptional elongation. Moreover, UBE2O influences energy homeostasis in skeletal muscle through its control over AMPKα levels, and its dysregulation has been implicated in neurodegenerative contexts such as Alzheimer’s disease. Earlier reports initially proposed its ubiquitin‐conjugating activity, while recent reviews have highlighted its capacity to function as an E2/E3 hybrid enzyme targeting diverse substrates. Finally, although one study focused on enhancing angiogenesis for wound repair provides an ancillary perspective on tissue regeneration, the precise role of UBE2O in this area remains to be clarified."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nazar Mashtalir, Salima Daou, Haithem Barbour, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "UBE2O targets Mxi1 for ubiquitination and degradation to promote lung cancer progression and radioresistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41418-020-00616-8"}], "href": "https://doi.org/10.1038/s41418-020-00616-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32901121"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32901121"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xu Liu, Fei Ma, Chunxiao Liu, et al. 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