Contrasting roles of APE1 and APE2 in genome maintenance, cancer development, and therapeutic targeting

Apurinic/apyrimidinic endonucleases - APE1 and APE2 are central to genome maintenance and the cellular DNA damage response, with expanding relevance in cancer biology. APE1 is the primary endonuclease in base excision repair and functions as a redox coactivator of transcription factors. In contrast, APE2 exhibits PCNA dependent 3'-5' exonuclease and 3'-phosphodiesterase activities, contributing to microhomology-mediated end joining, ATR-Chk1 activation, and immunoglobulin diversification. Both enzymes are often deregulated in cancer: APE1 is frequently overexpressed, drives tumor progression and chemoresistance, while APE2 is similarly upregulated in multiple malignancies. APE1 can be targeted by redox-specific or endonuclease inhibitors, with early clinical evidence of biological activity and tolerability. Although APE2-specific inhibitors remain in early development, emerging synthetic lethality data and preclinical studies highlight APE2 as a novel clinical target in breast cancer type 1/2 susceptibility (BRCA)-mutated cancers. This review discusses the structural and functional roles of APE1 and APE2, their contributions to cancer biology and therapeutics, recent advances in inhibitor development, and future strategies for precision oncology.