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 DNAdamage. We have previously reported that E2F1 and E2F2, the latter specifically in neuronal cells, aretranscriptionally induced after DNA damage. This upregulation, which relies on ATM/ATR kinases activity and isconserved among different species, leads to increased E2F1 and E2F2 protein levels as a consequence of de novoprotein synthesis. In the present study, we evaluated the significance of E2F1 and E2F2 induction in the maintenanceof genome integrity in neuronal cells. Ectopic expression of these E2Fs reduces the level of DNA damage followinggenotoxic treatment, while ablation of E2F1 and E2F2 leads to the accumulation of DNA lesions and increasedapoptotic response. Cell viability and DNA repair capability in response to DNA damage induction are also reducedby the E2F1 and E2F2 deficiencies. In addition, E2F1 and E2F2 accumulate at sites of oxidative and UV-inducedDNA damage, and interact with γH2AX DNA repair factor. Finally, as it was previously established for E2F1, weshow that E2F2 downregulation impairs Rad51 foci formation upon genotoxic insult. The results presented hereunveil a new mechanism involving E2F1 and E2F2 in the maintenance of genomic stability in response to DNAdamage in neuronal cells.