The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability. Here we present the genetic interaction profiles of APE2, APE1, and TDP1 deficiency coupled to biochemical and structural dissection of APE2. We conclude that the main role of APE2 is to reverse blocked 3′ DNA ends, problematic lesions that preclude DNA synthesis. Our work also suggests that TOP1 processing of genomic ribonucleotides is the main source of 3′-blocking lesions relevant to APEX2-BRCA1/2 synthetic lethality. The exquisite sensitivity of BRCA-deficient cells to 3′ blocks indicates that they represent a tractable vulnerability in homologous recombination-deficient tumor cells.

APEX2基因编码 APE2，这是一种与 APE1 相关的核酸酶，APE1 是一种在碱基切除修复中发挥作用的无嘌呤/无嘧啶核酸内切酶。 APE2 的缺失对于BRCA1或BRCA2突变的细胞来说是致命的，这使得 APE2 成为同源重组缺陷型癌症的主要靶标。然而，由于人们对 APE2 在 DNA 修复中的功能知之甚少，因此尚不清楚为什么 BRCA 缺陷细胞需要 APE2 来维持活力。在这里，我们展示了 APE2、APE1 和 TDP1 缺陷的遗传相互作用概况以及 APE2 的生化和结构解剖。我们得出结论，APE2 的主要作用是逆转 3' DNA 末端阻断，即阻碍 DNA 合成的问题性病变。我们的工作还表明，基因组核糖核苷酸的 TOP1 加工是与APEX2-BRCA1/2合成致死相关的 3' 阻断损伤的主要来源。 BRCA 缺陷细胞对 3' 区块的高度敏感性表明它们代表了同源重组缺陷肿瘤细胞中易于处理的脆弱性。