DNA Replication Checkpoint Signaling

Abstract

Eukaryotic cells respond to perturbations in DNA replication by activating checkpoint signaling pathways to maintain genome integrity. This ensures complete and accurate replication of DNA before chromosomes segregate during mitosis. Checkpoints can be activated upon replication fork stalling or DNA damage, both from extrinsic or intrinsic sources. Studies from several different eukaryotic model organisms have provided a clear picture of the broadly conserved replication checkpoint. In particular, the ATR and Chk1 kinases emerge as key regulators that mediate cellular responses to replication stress. The replication checkpoint stabilizes replication forks, coordinates repair, and induces a G2/M cell cycle arrest. It also promotes activation of nearby dormant origins while inhibiting late origin activation throughout the genome, which lengthens the S phase. In this chapter, we focus on the activation of replication checkpoint signaling, emphasizing its effect on origin activation.