{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBE2N (also known as Ubc13) is a critical E2 ubiquitin‐conjugating enzyme dedicated to assembling Lys63‐linked polyubiquitin chains that orchestrate non‐proteolytic signaling events. Working in partnership with cofactors such as MMS2, UEV1A, or Ube2V2, UBE2N precisely regulates ubiquitin chain assembly required for the recruitment of DNA repair complexes and checkpoint mediators. Structural and biochemical studies have revealed dynamic conformations of UBE2N∼Ub conjugates and detailed the specific interfaces mediating its association with RING ligases such as RNF8 and RNF4 to facilitate efficient double‐strand break processing, homologous recombination, and proper cell cycle control. Moreover, evolutionary conservation studies in yeast and mammalian systems underline its indispensable role in error‐free postreplicative repair and in modulating key substrates including MDC1 and p53."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical role in DNA repair, UBE2N is a central regulator of innate immune and inflammatory signaling. By partnering with a range of RING‐type E3 ligases including TRAF6, RNF167, and others associated with the RIG-I pathway, it promotes the formation of unanchored and substrate‐conjugated Lys63‐linked ubiquitin chains that are essential for NF-κB activation, antiviral responses, and proper mitochondrial quality control via Parkin-mediated mitophagy. Its activity is further modulated by various posttranslational modifications such as ISGylation and by deubiquitinating enzymes including OTUB1, which can suppress UBE2N-driven ubiquitination. In parallel, UBE2N-dependent ubiquitination events regulate receptor internalization and endoplasmic reticulum-associated degradation, thereby coordinating cellular responses to stress and inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulation of UBE2N has emerged as a common theme in diverse pathological conditions, including several types of cancer and neurodegenerative diseases. Aberrant UBE2N expression or activity influences tumor cell survival, metastasis, and chemoresistance in breast, ovarian, bladder, and prostate cancers by modulating pathways that govern p53 activity, cell cycle progression, and receptor turnover. Moreover, non-coding RNAs that target UBE2N—as well as mutations affecting its interaction with E3 ligases—further contribute to oncogenic signaling and therapy resistance, as demonstrated in studies employing patient-derived organoids and acute myeloid leukemia models. In neurodegenerative disorders such as Alzheimer’s disease and Lafora disease, defects in UBE2N-mediated ubiquitination contribute to the accumulation of misfolded proteins and neurotoxicity, underscoring its broad impact on cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bin Wang, Stephen J Elledge "}, {"type": "b", "children": [{"type": "t", "text": "Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0710061104"}], "href": "https://doi.org/10.1073/pnas.0710061104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18077395"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18077395"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Guang Yu Zhao, Eiichiro Sonoda, Louise J Barber, et al. 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