From these experiments it is not clear that streptavidin remains bound to the substrate after CMG passage, as invoked by the bypass mechanism proposed by the authors. This can be addressed by placing the 32P-label on the modified strand of the DNA substrate to observe the generation of single-stranded streptavidin-DNA products, and by performing the reactions in the presence of excess free biotin to trap displaced streptavidin. This seems particularly relevant, as the experiment in Figure 5—figure supplement 1 detects significant Mcm10-dependent bypass of blocks even on the leading strand – how do the authors explain this latter observation?