{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The broad spectrum of studies indicates that CUL4A functions as the essential scaffold component of CRL4 (cullin‐RING) ubiquitin ligase complexes that orchestrate the ubiquitination and proteasomal degradation of a multitude of substrate proteins. In these multi‐subunit complexes, CUL4A associates with the adaptor DDB1, the RING‐finger protein ROC1, and diverse substrate receptors (including DDB2, DET1, WD40‐repeat proteins, and CRBN) to direct turnover of proteins involved in DNA repair, chromatin remodeling, cell cycle progression, transcriptional control, and antiviral defense."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of nucleotide excision repair and chromatin dynamics, CUL4A‐based complexes facilitate the ubiquitination of histones and damage recognition proteins, such as DDB2 and XPC, thereby regulating the accessibility of damaged DNA for repair processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": " Moreover, CRL4 complexes targeting cell cycle regulators—including Set8 and p21—ensure proper progression through S phase and maintenance of genomic stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n CUL4A complexes are also hijacked by viruses to counteract host defenses. For instance, viral proteins such as HIV‐1 Vpr and hepatitis B virus HBx engage the CUL4A–DDB1–ROC1 apparatus to induce degradation of antiviral factors (e.g. SAMHD1, SMC5/6) and enforce a cellular environment conducive to viral replication."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, CUL4A participates in the regulation of key transcription factors. Its incorporation into complexes that target proteins such as c‐Jun and regulate the activity of epigenetic modifiers (including PRMT5) links CUL4A to cell proliferation and oncogenic signaling. Deregulation of CUL4A activity has been associated with tumor progression—for example, by promoting epithelial–mesenchymal transition through modulation of histone marks at the ZEB1 promoter—and by influencing the stability of tumor suppressors such as p53 and MDM2."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, additional investigations have revealed that CUL4A function extends to modulating the levels of substrates involved in metabolic and stress‐responsive pathways (for example, through CRL4 complexes containing CRBN or targeting REDD1), thereby integrating diverse signals that impact cell growth and survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "20"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore that CUL4A is a versatile and central regulator of ubiquitin‐dependent proteolysis, which is indispensable for maintaining genomic integrity, controlling cell cycle transitions, modulating transcriptional programs, and mediating host–virus interactions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Regina Groisman, Jolanta Polanowska, Isao Kuraoka, et al. 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