The dynamics of Atm signalling dictate cellular fate decisions after DNA damage

DNA damage activates diverse cellular responses – either protective or deleterious –that ultimately promote or inhibit proliferation. How the distinct responses conferring crucial cell fate decisions are chosen is unclear. Using a systems approach, we demonstrate that the dynamic features of Atm dependent DNA double-strand break (DSB) signalling response dictate cellular outcome. Combining temporal phosphoproteome and nascent transcriptome analyses after low or high DNA-damage-load, we discovered that some responses, such as Tp53 activation, have an activation threshold and others arise independently of DNA-damage-load. Using DSB repair deficient cells, we show that persistent DSBs alter the kinetics – but not the amplitude – of Atm signalling. Thus, we demonstrate that pathway choices are dictated by the signalling dynamics and hence cell fate decisions are responsive to DNA-damage-load and repair capacity of the cells.