DNA polymerase ϵ links the DNA replication machinery to the S phase checkpoint

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Inhibition of DNA synthesis induces transcription of DNA damage -inducible genes and prevents mitotic entry through the action of the S phase checkpoint. We have isolated a mutant, dun2, defective for both of these responses. DUN2 is identical to POL2, encoding DNA polymerase ϵ (pol ϵ). Unlike sadl mutants defective for multiple cell cycle checkpoints, pol2 mutants are defective only for the S phase checkpoint and the activation of DUNI kinase necessary for the transcriptional response to damage. Interallelic complementation and mutation analysis indicate that pol ϵ contains two separable essential domains, an N-terminal polymerase domain and a C-terminal checkpoint domain unique to ϵ polymerases. We propose that DNA pol ϵ acts as a sensor of DNA replication that coordinates the transcriptional and cell cycle responses to replication blocks.