{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRAD23A, the human homolog of yeast Rad23, is a multifunctional protein central to both nucleotide excision repair (NER) and the ubiquitin–proteasome system. Its modular design—with an N‐terminal ubiquitin‐like (UBL) domain and one or more C‐terminal ubiquitin‐associated (UBA) domains—provides the structural basis for its dual roles. Structural studies show that the UBA domains adopt compact three‐helix bundles with conserved hydrophobic patches that likely serve as common protein–protein interaction surfaces for ubiquitin recognition, while the UBL domain mimics ubiquitin to mediate high‐affinity binding to proteasomal subunits such as S5a. In the context of NER, RAD23A facilitates DNA damage recognition by modulating factors like XPC, and its deficiency renders cells more sensitive to ultraviolet irradiation and disturbs cell cycle progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n\nBeyond its role in DNA repair, RAD23A functions as a shuttle factor that recognizes polyubiquitinated substrates via its UBA domains and delivers them to the proteasome through its UBL domain. Quantitative and structural analyses reveal that intramolecular interactions between its domains are disrupted upon binding proteasomal components, thereby enhancing its ability to capture and target substrates—such as the tumor suppressor p53—for regulated degradation. Moreover, RAD23A interacts with other ubiquitin‐receptor proteins and components of the ubiquitin fusion degradation (UFD) pathway, thereby integrating and modulating protein turnover in diverse cellular contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n\nRecent findings have broadened the spectrum of RAD23A functions. It has been identified as a histone demethylase that specifically removes methyl groups from histone H4K20, thereby influencing epigenetic control of gene expression. In parallel, RAD23A contributes to the regulation of antiviral signaling by interacting with key adaptor proteins (e.g. TRAF2) to down‐regulate proinflammatory cytokine production. Its binding to viral proteins—most notably the HIV-1 accessory factor Vpr—underscores a role in subverting host defense mechanisms and promoting viral replication in non-dividing cells. Furthermore, RAD23A helps regulate cell cycle checkpoints by facilitating the degradation of factors such as Chk1, and it modulates epithelial–mesenchymal transition through targeting of proteins like Twist1, implicating it in cancer cell migration, chemoresistance, and maintenance of cellular homeostasis. High-resolution structural investigations using X‐ray crystallography and NMR spectroscopy have provided detailed insights into the dynamic conformations of its UBL and UBA domains that underpin these diverse functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Robert T Elder, Xiang-qian Song, Mingzhong Chen, et al. 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