Human replisomes direct a dedicated leading-strand primase for fork restart.

CMG (CDC45-MCM-GINS) helicase directs PRIMPOL to enable efficient human replication fork restart, and disrupting their interaction abolishes restart in vitro and PRIMPOL-dependent DNA damage tolerance in cells.

• Why it matters: Leading-strand synthesis failures stall replication forks, and restarting/protecting stalled forks is linked to genomic instability; how PRIMPOL is coordinated by the replisome is unresolved.
• What they did: Using purified human proteins to reconstitute fork stalling and restart, the study tested PRIMPOL function with CMG and found PRIMPOL directly binds CMG; cryo-EM shows CMG targets PRIMPOL for leading-strand priming.
• The result: CMG-PRIMPOL binding is required for fork restart in vitro and for PRIMPOL-dependent DNA damage tolerance in human cells, while PRIMPOL–replication protein A interaction is not critical in this reconstituted system.

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