The ZGRF1 Helicase Promotes Recombinational Repair of Replication-Blocking DNA Damage in Human Cells

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. [Display omitted] •The human ZGRF1 gene encodes a 5′-to-3′ DNA helicase•ZGRF1 null cells are sensitive to mitomycin C and camptothecin•ZGRF1 promotes homologous recombination and sister chromatid exchange•ZGRF1 physically interacts with RAD51 and stimulates strand exchange by RAD51-RAD54 DNA helicases are important for DNA repair processes. Here, Brannvoll et al. show that ZGRF1 is a 5′-to-3′ DNA helicase that promotes the resolution of replication-blocking DNA lesions by homologous recombination. ZGRF1 is recruited to sites of DNA damage and directly stimulates the RAD51 recombinase.