| Apurinic/apyrimidinic endonuclease 1 (APE1, also known as APEX1 or Ref‑1) is the major abasic site endonuclease in mammalian cells and a multifunctional nuclear protein that integrates base excision repair with redox regulation of transcription factors and broader DNA damage response signaling. The protein belongs to the divalent metal‑dependent α/β phosphoesterase superfamily and contains a structured C‑terminal catalytic core with active‑site residues and flexible loops that mediate DNA binding, lesion recognition, and incision chemistry, together with a unique N‑terminal segment that provides nuclear targeting and interaction interfaces for partner proteins and modulates localization and regulatory functions. APE1 recognizes abasic sites generated during base excision repair or by spontaneous base loss, flips the lesion into a compact active site pocket, and cleaves the phosphodiester backbone 5′ to the abasic nucleotide to create a nick with 3′‑hydroxyl and 5′‑deoxyribose phosphate termini that are suitable for subsequent gap filling by DNA polymerase β and ligation, thereby preventing accumulation of toxic AP sites and single‑strand breaks. The enzyme also removes a range of 3′‑blocking groups such as 3′‑phosphates and 3′‑phosphoglycolates through 3′‑repair diesterase and 3′‑exonuclease activities, directly contributing to processing of DNA ends arising from oxidative and radiation‑induced damage and facilitating completion of multiple repair pathways. Additional nucleotide incision repair activity enables APE1 to incise some oxidatively damaged bases directly without prior glycosylase action, expanding its role beyond canonical BER and connecting it to alternative repair routes for oxidized purines and pyrimidines. A redox‑regulatory function resides in the N‑terminal region, where APE1 maintains critical cysteine residues of transcription factors such as AP‑1, NF‑κB, HIF‑1α, and others in a reduced state that favors DNA binding, thereby coupling cellular redox status and DNA damage to transcriptional responses that govern inflammation, angiogenesis, and stress adaptation. APE1 interacts with numerous DNA repair and chromatin‑associated partners, forming a central hub in the BER interactome that coordinates lesion recognition, repair synthesis, and chromatin access and that also interfaces with ATM/ATR‑mediated checkpoint pathways, positioning APE1 as a regulator of genome stability and cell fate after genotoxic stress. Tight regulation of APE1 expression, subcellular distribution, and post‑translational modification is essential for cell viability; depletion is lethal in mouse embryos and compromises resistance to oxidative and alkylation damage, while abnormal overexpression, mislocalization, or altered activity are reported in a range of cancers and neuropathologies and associate with therapy resistance and disease susceptibility. |
