E2F4, a transcription factor with a prominent role in cell homeostasis, can be phosphorylated by the stress kinase p38MAPK at the Thr248/Thr250 motif, while the Thr248Ala/Thr250Ala E2F4 mutant (E2F4DN) triggers multifactorial therapeutic effects in a murine model of Alzheimer's disease. We hypothesized that the mechanism of action of this therapy relays on the phosphorylation of the Thr248/Thr250 motif under stress conditions, which prevents the homeostatic function of E2F4, while exogenous E2F4DN expression can restore this function. To provide support to this hypothesis, we have focused on genotoxicity induced by camptothecin (CPT) in N2a neuroblastoma-derived neurons, as a paradigm of cell stress followed by cell death. Here we show that, in these cells, p38MAPK becomes activated 6 h after CPT treatment, followed by E2F4 phosphorylation in the Thr248/Thr250 motif. The effect of this phosphorylation in apoptosis was tested by overexpressing wild-type E2F4 (E2F4WT), its Thr248Glu/Thr250Glu phosphomimetic (E2F4CA) or E2F4DN in CPT-treated N2a neurons, followed by quantification of procaspase-3 cleavage. E2F1, which was used as a positive control, induced a statistically-significant increase of procaspase-3 cleavage 32 h after CPT treatment. This was mimicked by either E2F4WT or E2F4CA, while E2F4DN expression inhibited this effect through a Cited2-dependent mechanism. Pharmacological p38MAPK inhibition prevented cell death by E2F4WT but not by E2F4CA, confirming the requirement of E2F4 phosphorylation for cell death in these cells. We conclude that the phosphorylation of E2F4 facilitates the death of N2a neurons carrying DNA damage, while E2F4DN maintains the homeostatic function of E2F4 under stress conditions.