Signaling of DNA Replication Stress Through the ATR Checkpoint

DNA replication is one of the most fundamental cellular processes. Faithful replication of the entire genome is a daunting task, especially when cells are under intrinsic or extrinsic stress. To maintain genomic stability during DNA replication, eukaryotic cells have evolved a sophisticated signaling network called the checkpoint to orchestrate cellular responses to different types of DNA replication problems. The ATR kinase is the master regulator of the DNA replication checkpoint. Activated by a wide spectrum of DNA damage and replication problems, ATR and its effector kinase Chk1 regulate and coordinate DNA replication, DNA repair, and cell cycle transitions. Mounting evidence has suggested that the ATR checkpoint pathway is crucial for the suppression of genomic instability and sustained cell survival. In this review, we will discuss the recent findings on how the ATR pathway is activated by replication stress and how this pathway functions to suppress genomic instability during DNA replication.