DNA Damage and Replication Stress Checkpoints

DNA damage checkpoints are key regulatory signaling cascades that arrest cell cycle progression upon DNA damage or upon DNA replication stalling and allow time for repair or correction. Failure to elicit these checkpoints can lead to genomic instability that can result in cell death or mutations, ultimately leading to diseases such as cancer. Components of the DNA damage checkpoint are attractive targets for precision medicine to treat cancers. Over the last several years, cutting-edge structural techniques have provided molecular insights into the highly coordinated checkpoint signaling that occurs in response to DNA damage or other obstacles to replication progression. This review summarizes our current mechanistic understanding of the DNA damage checkpoint in eukaryotes, with an emphasis on the sensor kinases ATM (Tel1) and ATR (Mec1), highlighting structure–function and cellular studies.