Replication-blocking DNA lesions are particularly toxic to proliferating cells because they can lead to chromosome mis-segregation if not repaired prior to mitosis. In this study, we report that ZGRF1 null cells accumulate chromosome aberrations following replication perturbation and show sensitivity to two potent replication-blocking anticancer drugs: mitomycin C and camptothecin. Moreover, ZGRF1 null cells are defective in catalyzing DNA damage-induced sister chromatid exchange despite accumulating excessive FANCD2, RAD51, and γ-H2AX foci upon induction of interstrand DNA crosslinks. Consistent with a direct role in promoting recombinational DNA repair, we show that ZGRF1 is a 5′-to-3′ helicase that catalyzes D-loop dissociation and Holliday junction branch migration. Moreover, ZGRF1 physically interacts with RAD51 and stimulates strand exchange catalyzed by RAD51-RAD54. On the basis of these data, we propose that ZGRF1 promotes repair of replication-blocking DNA lesions through stimulation of homologous recombination.

阻止复制的DNA损伤对增殖细胞特别有毒，因为如果在有丝分裂之前不进行修复，它们会导致染色体错误分离。在这项研究中，我们报告ZGRF1空细胞在复制扰动后积累染色体畸变，并显示出对两种有效的复制阻断抗癌药物：丝裂霉素C和喜树碱的敏感性。此外，ZGRF1尽管在诱导链间DNA交联时积累了过多的FANCD2，RAD51和γ-H2AX病灶，但空细胞在催化DNA损伤诱导的姐妹染色单体交换方面仍存在缺陷。与促进重组DNA修复的直接作用一致，我们表明ZGRF1是5'到3'解旋酶，催化D环解离和霍利迪结分支迁移。此外，ZGRF1与RAD51发生物理相互作用，并刺激RAD51-RAD54催化的链交换。基于这些数据，我们建议Z​​GRF1通过刺激同源重组促进复制阻滞性DNA损伤的修复。