ATR and cancer: We addressed the elusive genotype–phenotype and structure–function relationships of ATM/ATR proteins by examining the conserved ATM/ATR residues mutated in cancer and performing an unbiased functional genetic analysis of MEC1. Our analyses unveil that only a few of the ATM/ATR residues implicated in cancer are in the active site of the respective enzyme complex, suggesting that loss of the intrinsic kinase activity is infrequent in carcinogenesis (Fig. 4c, d and Supplementary Fig. 4a, b).