Augmenting the cytotoxic effects of replication stress to treat cancer may take many directions, such as inhibiting upstream checkpoint factors like ATM and ATR [28,30,274,275,276], directly inhibiting replication fork restart nucleases MUS81, EEPD1, or Metnase [166,167,277], and exploiting synthetic lethal relationships such as MUS81-PARP [168], MUS81-BRCA2 [126], BRCA2-RAD52 [198,199], and TATDN2-BRCA1 [66]. The gene discussed is ATM; the disease is cancer.