The chapter discusses the role of cell-cycle checkpoints in ensuring the accuracy of DNA replication and repair, focusing on the ATM and ATR kinases. These kinases are crucial for detecting and responding to DNA damage, particularly in eukaryotic cells. The checkpoints coordinate cell-cycle progression with DNA repair, often leading to cell arrest or apoptosis if damage is severe. ATM and ATR are part of a broader signaling pathway that links DNA damage to the activation of downstream target proteins. The chapter highlights the structural and functional similarities between ATM and ATR, both belonging to the phosphoinositide 3-kinase-related (PIKK) family. ATM and ATR are involved in phosphorylating specific residues on proteins like p53, Chk2, and MDM2, which play key roles in regulating cell cycle checkpoints and DNA repair. The chapter also explores the mechanisms by which ATM and ATR are recruited to DNA damage sites and the complexes they form with other proteins, such as BRCA1, to enhance their signaling functions. The functional consequences of ATM and ATR phosphorylation on these proteins are discussed, particularly in the context of the G1, S, and G2 checkpoints. ATM is primarily involved in the G1 checkpoint, while ATR plays a more diverse role across all phases of the cell cycle. The chapter emphasizes the importance of these checkpoints in maintaining genomic stability and preventing the progression of damaged cells to mitosis.The chapter discusses the role of cell-cycle checkpoints in ensuring the accuracy of DNA replication and repair, focusing on the ATM and ATR kinases. These kinases are crucial for detecting and responding to DNA damage, particularly in eukaryotic cells. The checkpoints coordinate cell-cycle progression with DNA repair, often leading to cell arrest or apoptosis if damage is severe. ATM and ATR are part of a broader signaling pathway that links DNA damage to the activation of downstream target proteins. The chapter highlights the structural and functional similarities between ATM and ATR, both belonging to the phosphoinositide 3-kinase-related (PIKK) family. ATM and ATR are involved in phosphorylating specific residues on proteins like p53, Chk2, and MDM2, which play key roles in regulating cell cycle checkpoints and DNA repair. The chapter also explores the mechanisms by which ATM and ATR are recruited to DNA damage sites and the complexes they form with other proteins, such as BRCA1, to enhance their signaling functions. The functional consequences of ATM and ATR phosphorylation on these proteins are discussed, particularly in the context of the G1, S, and G2 checkpoints. ATM is primarily involved in the G1 checkpoint, while ATR plays a more diverse role across all phases of the cell cycle. The chapter emphasizes the importance of these checkpoints in maintaining genomic stability and preventing the progression of damaged cells to mitosis.