{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ATAD5, the human ortholog of yeast Elg1, is emerging as a central regulator of genome integrity by coordinating DNA replication, repair, and cell‐cycle progression. Its key function is to unload the sliding clamp PCNA (proliferating cell nuclear antigen) from chromatin at the end of replication or when the fork encounters stress, thereby regulating the lifespan of replication factories and ensuring timely S‐phase progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, ATAD5 facilitates proper PCNA deubiquitination—a process essential for preventing replication‐associated genomic instability and tumorigenesis, as shown by studies in murine models and human cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Furthermore, by unloading PCNA from DNA, ATAD5 prevents its persistent accumulation, which would otherwise lead to collisions between the replication and transcription machineries, excessive formation of R‐loops, and consequent replication stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Under conditions of fork stalling, ATAD5 supports replication restart by promoting RAD51 recruitment in an ATR‐dependent manner, highlighting its role in the repair of stressed forks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Its activity is further modulated by chromatin regulators—for example, BRD4 binds both acetyl‐histones and ATAD5 to inhibit PCNA unloading, thereby fine‐tuning the amount of chromatin‐bound PCNA during nascent DNA formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the context of human disease, germline missense variants in ATAD5 are enriched in ovarian cancers, and ATAD5 is also encompassed within NF1 microdeletion regions that contribute to more severe clinical phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, ATAD5 is implicated in the repair of oxidative DNA damage; its depletion leads to sustained PCNA retention during repair synthesis of reactive oxygen species–induced single‐strand breaks, fostering harmful nick structures."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, reviews and additional mechanistic studies have underscored that failure to unload PCNA appropriately—not only disrupts replication fork dynamics but also impairs proper checkpoint activation—thus linking ATAD5 dysfunction with genomic instability and cancer predisposition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kyoo-young Lee, Haiqing Fu, Mirit I Aladjem, et al. 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