(A) Cells are equipped with checkpoints that regulate cell cycle progression upon DNA damage. ATR and ATM are key upstream checkpoint kinases that co-ordinate the DDR in response to single-strand DNA (ssDNA) and double-strand breaks (DSBs), respectively. Whereas ATM can be activated throughout interphase (orange line), ATR activation is restricted to S/G2 phase (brown line). Contrary to interphase, DNA damage does not halt cell cycle progression in mitosis. (B) In response to DSBs, cells utilize two canonical pathways to repair DSBs. Whereas canonical non-homologous end joining (c-NHEJ) is active throughout interphase, homologous recombination (HR) allows for templated repair sister chromatids become present in S/G2 phase. When these canonical pathways are not active due to genetic or experimental perturbations, alternative repair pathways, including break-induced replication (BIR), single-strand annealing (SSA), and alternative end joining (Alt-EJ), will be employed. The absence of canonical repair pathways is reminiscent of the mitotic state, in which mitotic kinases CDK1 and PLK1 inactivate many HR and c-NHEJ factors through phosphorylation.