E2F1 and E2F2 induction in response to DNA damage preserves genomic stability in neuronal cells

CASTILLO DS; CAMPALANS A; RADICELLA JP; CÁNEPA ET; PREGI N

Rosario, Santa Fé

Congreso; L Reunión anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2014

E2F transcription factors regulate a wide range of biological processes, including the cellular response to DNA damage. We have previously reported that E2F1 and E2F2, the latter specifically in neuronal cells, are transcriptionally induced after DNA damage. This upregulation, which relies on ATM/ATR kinases activity and is conserved among different species, leads to increased E2F1 and E2F2 protein levels as a consequence of de novo protein synthesis. In the present study, we evaluated the significance of E2F1 and E2F2 induction in the maintenance of genome integrity in neuronal cells. Ectopic expression of these E2Fs reduces the level of DNA damage following genotoxic treatment, while ablation of E2F1 and E2F2 leads to the accumulation of DNA lesions and increased apoptotic response. Cell viability and DNA repair capability in response to DNA damage induction are also reduced by the E2F1 and E2F2 deficiencies. In addition, E2F1 and E2F2 accumulate at sites of oxidative and UV-induced DNA damage, and interact with gH2AX DNA repair factor. Finally, as it was previously established for E2F1, we show that E2F2 downregulation impairs Rad51 foci formation upon genotoxic insult. The results presented here unveil a new mechanism involving E2F1 and E2F2 in the maintenance of genomic stability in response to DNA damage in neuronal cells.