The molecular basis of replication fork restart via repriming by PRIMPOL.

PRIMPOL is recruited to stalled replication forks via interaction with the CMG helicase complex (CDC45-MCM2-7-GINS), enabling CMG-dependent repriming and primer handover to polymerase ε.

• Why it matters: The mechanism and targeting of PRIMPOL at stalled forks are unclear, including where it binds on single-stranded DNA and how it is regulated to limit error-prone synthesis.
• What they did: Using real-time single-molecule imaging in nuclear extracts that recapitulate genome maintenance, the authors visualized fork restart and tested PRIMPOL recruitment and primer handover, including near-physiological concentrations and conditions with checkpoint activation.
• The result: Near-physiological PRIMPOL reprimes leading strands in a CMG-dependent manner and polymerase ε extends them without DNA damage checkpoint signalling, while PRIMPOL overexpression or checkpoint activation promotes a secondary CMG-independent mode using polymerase δ.

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