APE2: catalytic function and synthetic lethality draw attention as a cancer therapy target

AP endonuclease 2 (APE2, APEX2 or APN2) is an emerging critical protein involved in genome and epigenome integrity. Whereas its catalytic function as a nuclease in DNA repair is widely accepted, recent studies have elucidated the function and mechanism of APE2 in the immune response and DNA damage response. Several genome-wide screens have identified APE2 as a synthetic lethal target for deficiencies of BRCA1, BRCA2 or TDP1 in cancer cells. Due to its overexpression in several cancer types, APE2 is proposed as an oncogene and could serve as prognostic marker of overall survival of cancer treatment. However, it remains to be discovered whether and how APE2 catalytic function and synthetic lethality can be modulated and manipulated as a cancer therapy target. In this review, we provide a current understanding of alterations and expression of APE2 in cancer, the function of APE2 in the immune response, and mechanisms of APE2 in ATR/Chk1 DNA damage response. We also summarize the role of APE2 in DNA repair pathways in the removal of heterogenous and complexed 3'-termini and MMEJ. Finally, we provide an updated perspective on how APE2 may be targeted for cancer therapy and future directions of APE2 studies in cancer biology.