{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FAN1 (Fanconi‐associated nuclease 1) is a structure‐specific nuclease that plays a critical role in the repair of DNA interstrand cross‐links (ICLs) and in the maintenance of genome stability. Recruited to sites of DNA damage through its ubiquitin‐binding (UBZ) domain and by direct interaction with monoubiquitinated FANCD2, FAN1 exhibits both 5′→3′ exonuclease and structure‐specific endonuclease activities that allow it to process nicked, branched, and 5′ flap DNA structures during ICL unhooking and subsequent repair."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its canonical function in ICL repair, FAN1 modulates the expansion of repetitive DNA sequences. Elevated FAN1 expression has been shown to delay the onset and slow the progression of Huntington’s disease by reducing somatic CAG repeat expansion, while its nuclease activity is essential for protection in models of repeat expansion disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n FAN1 also contributes to tumor suppression and genome integrity, as mutations in FAN1 have been linked to hereditary colorectal and pancreatic cancers and are associated with neurodevelopmental and neuropsychiatric phenotypes when functionally critical domains are affected."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, loss‐of‐function mutations in FAN1 underlie karyomegalic interstitial nephritis (KIN), a rare kidney disorder characterized by chronic renal fibrosis and genomic instability, as demonstrated in both human patients and corresponding murine models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural studies further reveal that FAN1 can form homodimers—a configuration mediated by a flexible loop region—that is critical for the efficient cleavage of long 5′ flap substrates, underscoring the importance of its oligomeric state for proper DNA processing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, additional findings indicate that FAN1 is subject to cell cycle–dependent regulation, including degradation during mitotic exit via APC/C activity, and functions in the coordination of replication fork restart processes. Collectively, these studies establish FAN1 as a multifaceted genome guardian that integrates ICL repair, replication fork recovery, repeat expansion modulation, and cellular responses to DNA double‐strand breaks, with its dysfunction contributing to diverse disease pathologies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "20"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Agata Smogorzewska, Rohini Desetty, Takamune T Saito, et al. 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