McMahon Anne, Zhao Jianjun, Yan Shan
Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
NAR Cancer. 2023 Feb 6;5(1):zcad006. doi: 10.1093/narcan/zcad006. eCollection 2023 Mar.
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.
脱嘌呤/脱嘧啶核酸内切酶2（APE2、APEX2或APN2）是一种在基因组和表观基因组完整性方面发挥关键作用的新兴蛋白质。虽然其作为核酸酶在DNA修复中的催化功能已被广泛认可，但最近的研究阐明了APE2在免疫反应和DNA损伤反应中的功能及机制。多项全基因组筛选已将APE2确定为癌细胞中BRCA1、BRCA2或TDP1缺陷的合成致死靶点。由于APE2在多种癌症类型中过表达，它被认为是一种癌基因，可作为癌症治疗总体生存的预后标志物。然而，APE2的催化功能和合成致死性是否以及如何能作为癌症治疗靶点进行调控和操纵仍有待发现。在本综述中，我们阐述了目前对APE2在癌症中的改变和表达、其在免疫反应中的功能以及在ATR/Chk1 DNA损伤反应中的机制的理解。我们还总结了APE2在DNA修复途径中去除异源和复合3'末端及微同源末端连接中的作用。最后，我们提供了关于如何将APE2作为癌症治疗靶点的最新观点以及APE2在癌症生物学研究中的未来方向。
