(A) Sensitivity of FANCJ HeLa FIT knock-out cells (FJ–/–) complemented with different FANCJ constructs to CX-5461 treatment. In the graphs, the mean values of three independent experiments are depicted. For raw values, standard deviations and statistical analysis see S4 Table. CX, CX-5461; WT, wild-type; KR, K52R; CS, C283S; CR, C283R; MI, M299I; LF, L340F; AP, A349P. (B) Model showing wild-type FANCJ able to resolve G4 structures on the templating strand during DNA replication, which would allow continuous DNA synthesis (upper panel). In contrast, the inability of FeS cluster-deficient FANCJ to efficiently resolve G4 structures would lead to polymerase stalling and persistent replisome-associated G4 structures (lower panel).