{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBR5 is a large, HECT‐domain ubiquitin ligase that plays critical roles in safeguarding genome integrity. Multiple studies have shown that UBR5 regulates the DNA damage response by controlling the accumulation and spatial distribution of key factors at double‐strand breaks, such as by limiting RNF168 spreading and thereby ensuring localized histone ubiquitylation. In addition, UBR5 participates in cell‐cycle regulation by modulating the stability or activity of checkpoint kinases (e.g. CHK2), transcriptional co‐factors (e.g. p53) and even telomerase catalytic subunits through phosphorylation‐dependent mechanisms; together, these activities help maintain proper replication dynamics and genomic stability during both S phase and mitosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its pivotal role in DNA repair and cell‐cycle checkpoints, UBR5 modulates diverse transcriptional and signaling pathways. It fine‐tunes the stability of key regulators by ubiquitinating substrates involved in Wnt/β‐catenin signaling, nuclear hormone receptor turnover (including receptors such as RARA, RXRA, and PXR) and transcriptional elongation via its interactions with factors like CDK9 and TFIIS. UBR5 also influences the assembly of multiprotein complexes at enhancers and even participates in the formation of primary cilia through targeted ubiquitylation of centrosomal proteins—demonstrating its broad regulatory reach over gene expression and cellular signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant expression, mutation, and even gene fusions of UBR5 have been widely implicated in oncogenesis across many tumor types. Recurrent mutations and frameshift events—as observed in mantle cell lymphoma—coupled with overexpression of UBR5 are linked to tumor progression in triple‐negative breast cancer, ovarian, gastric, pancreatic, colorectal, laryngeal and nasopharyngeal carcinomas, as well as melanoma. These oncogenic alterations contribute to enhanced tumor cell proliferation, metastasis, and therapy resistance—partly by suppressing apoptotic proteins (for example, via MOAP‐1 downregulation), modulating oncogene thresholds (such as MYC activity) and by reprogramming tumor–stroma interactions. Moreover, emerging structural studies reveal that UBR5 can form higher‐order oligomers, potentially influencing its substrate recruitment and catalytic efficiency, which may further underlie its multifaceted roles in cancer pathophysiology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michelle J Henderson, Amanda J Russell, Samantha Hird, et al. 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