FEN1 (flap structure-specific endonuclease 1) is a critical DNA repair enzyme with 5'-flap endonuclease and 5'-3' exonuclease activities essential for genome stability 1. During DNA replication, FEN1 processes Okazaki fragments by cleaving 5'-overhanging flap structures generated when DNA polymerase encounters downstream fragments, threading the flap through its helical arch before cleavage 1. FEN1 also participates in long-patch base excision repair (LP-BER) by cleaving within apurinic/apyrimidinic site-terminated flaps 2. The enzyme prevents genome instability by processing replication intermediates and maintaining nascent DNA strand integrity, as PARP inhibition in FEN1-deficient cells reveals increased DNA strand discontinuities 2. FEN1 contributes to transcription-dependent DNA double-strand break formation through R-loop cleavage, particularly relevant in non-replicating neuronal cells where defects cause neurodegenerative disorders 3. In cancer, FEN1 exhibits dual roles: while serving as a tumor suppressor, its overexpression promotes cancer progression and chemotherapy resistance 45. FEN1 polymorphisms (-69G>A and 4150G>T) are associated with increased disease susceptibility across multiple conditions 6. Dysregulated FEN1 expression affects cellular senescence, with implications for neuroblastoma cisplatin sensitivity and cancer therapeutic strategies 54.