In CLL, we showed that ATM and TP53 defects are synthetically lethal with ATR loss (Figure 1) by constraining cells to repair large volumes of DSBs through nonhomologous end joining (NHEJ) [68], an error-prone, low-fidelity backup path that often results in further genomic aberrations [133]. The gene discussed is TP53; the disease is B-cell chronic lymphocytic leukemia.