The present invention is directed to compositions and methods regarding the signaling for the presence of DNA damage or replication stress and activating cell cycle checkpoints. Specifically, ATRIP was identified as an interactor with ATR, a member of the phosphatidylinositol kinase-related protein family that includes ATM and DNA-PK. In some embodiments, the present invention is directed to ATRIP and ATR acting as mutually dependent partners in cell cycle checkpoint signaling pathways.