The Notch signalling pathway regulates cell fate determination and can promote tumorigenesis. Vermezovic et al. found that the NOTCH1 receptor suppresses the activation of the DNA damage response (DDR) in nematodes and in human cells by inhibiting the kinase ataxia telangiectasia mutated (ATM). This required the nuclear localization of NOTCH1 but not its transcriptional activity, as cells with transcriptionally inactive NOTCH1 could inhibit ATM activation. NOTCH1 directly binds to the ATM regulatory domain FATC to inhibit its kinase activity. Furthermore, NOTCH1 inhibition promoted ATM-dependent apoptosis in irradiated acute lymphoblastic leukaemia cells, in which NOTCH1 has an oncogenic role, and ATM and NOTCH1 activities were inversely correlated in human breast cancers.