Mechanistic insights into how CMG helicase facilitates replication past DNA roadblocks

•Interaction of CMG helicase with DNA substrate dictates fate of replication fork.•Modified versus strict steric exclusion model has implications for CMG block bypass.•Replisome-associated factors may affect replisome bypass of bulky adducts.•CMG structural adjustments are required for fork traverse of interstrand cross-link.•Multiple mechanisms are responsible for bypass of replication obstacles in vivo.