A role for DNA polymerase theta in the timing of DNA replication

Although DNA polymerase theta (Pol theta) is known to carry out translesion synthesis and has been implicated in DNA repair, its physiological function under normal growth conditions remains unclear. Here we present evidence that Pol theta plays a role in determining the timing of replication in human cells. We find that Pol theta binds to chromatin during early G1, interacts with the Orc2 and Orc4 components of the Origin recognition complex and that the association of Mcm proteins with chromatin is enhanced in G1 when Pol theta is downregulated. Pol theta-depleted cells exhibit a normal density of activated origins in S phase, but early-to-late and late-to-early shifts are observed at a number of replication domains. Pol theta overexpression, on the other hand, causes delayed replication. Our results therefore suggest that Pol theta functions during the earliest steps of DNA replication and influences the timing of replication initiation.