{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBQLN4 acts as a key proteasomal shuttle factor that safeguards genomic stability by regulating DNA double‐strand break repair. Notably, UBQLN4 is phosphorylated by ATM and binds to ubiquitylated MRE11, thereby promoting the timely removal of MRE11 from damaged chromatin and curtailing homologous recombination repair. This function is critical in preventing non‐physiological recombination processes that can lead to genomic instability—a hallmark found in certain genetic diseases and cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in the DNA damage response, UBQLN4 contributes to cellular protein quality control. It mediates crosstalk between different degradation pathways by recruiting Ubqln1 to the core autophagy machinery, thereby facilitating autophagosome maturation, while also serving as a surveillance factor that targets mislocalized or misassembled transmembrane proteins for proteasomal degradation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, UBQLN4 demonstrates multifaceted roles. In gastric cancer, for instance, UBQLN4 can function as a tumor suppressor by activating the p53/p21 pathway, inducing cellular senescence, and arresting cell cycle progression through G1–S or G2/M checkpoints. Such actions are complemented by its ability to modulate the stability of key cell cycle regulators via the attenuation of proteasomal degradation, in part through its interactions with E3 ubiquitin ligases. Conversely, in esophageal squamous cell carcinoma and other tumor types, UBQLN4 overexpression has been associated with enhanced degradation of MRE11A, thereby impairing effective DNA repair and promoting chemoresistance. A broader pan‐cancer screening further highlights UBQLN4 upregulation as a prognostic marker and a potential biomarker for sensitivity to therapies such as PARP inhibitors, as well as a predictor of immunotherapy responses."}, {"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 genome maintenance and tumorigenesis, UBQLN4 is emerging as an important factor in other pathophysiological contexts. It facilitates viral infection by engaging with ER‐resident J proteins to capture and promote the cytosolic escape of nonenveloped viruses such as simian virus 40, thereby influencing infection efficiency. Furthermore, variants of UBQLN4 have been linked with neurodegenerative disorders like amyotrophic lateral sclerosis, where altered UBQLN4 function impairs proteasomal activity and disturbs the regulation of substrates critical for motor axon morphogenesis. Early investigations in non‐small cell lung cancer also suggest that UBQLN4 may have distinct roles in tumor biology that warrant further study."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ron D Jachimowicz, Filippo Beleggia, Jörg Isensee, et al. 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