An ATR and CHK1 kinase signaling mechanism that limits origin firing during unperturbed DNA replication

The 50,000 origins that replicate the human genome are selected from an excess of licensed origins. Firing licensed origins that would otherwise be passively replicated is a simple mechanism to recover DNA replication between stalled replication forks. This plasticity in origin use promotes genome stability if an unknown mechanism prevents a subset of origins from firing during unperturbed DNA replication. We describe ATR and CHK1 kinase signaling that suppresses a CDK1 kinase-dependent phosphorylation on the chromatin protein RIF1. The CDK1 kinase-dependent phosphorylation of RIF1 disrupts its interaction with PP1 phosphatase. Thus, ATR and CHK1 stabilize an interaction between RIF1 and PP1 that counteracts CDC7 and CDK2 kinase signaling at licensed origins. This mechanism limits origin firing during unperturbed DNA replication.