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

E2F transcription factors regulate a wide range of biological processes, including the cellular response to DNA damage. In the present study, we examined whether E2F family members are transcriptionally induced following treatment with several genotoxic agents, and have a role on the cell DNA damage response. We show a novel mechanism, conserved among diverse species, in which <i>E2F1</i> and <i>E2F2</i>, the latter specifically in neuronal cells, are transcriptionally induced after DNA damage. This upregulation leads to increased E2F1 and E2F2 protein levels as a consequence of <i>de novo</i> protein synthesis. Ectopic expression of these E2Fs in neuronal cells 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. Finally, E2F1 and E2F2 accumulate at sites of oxidative and UV-induced DNA damage, and interact with γH2AX DNA repair factor. As previously reported for E2F1, E2F2 promotes Rad51 foci formation, interacts with GCN5 acetyltransferase and induces histone acetylation following 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.

E2F转录因子（E2F transcription factors）可调控广泛的生物学过程，其中涵盖细胞对DNA损伤（DNA damage）的应答反应。本研究旨在探究E2F家族成员经多种遗传毒性剂处理后是否会被转录诱导，并在细胞DNA损伤应答中发挥功能。本研究揭示了一种在不同物种间保守存在的全新调控机制：E2F1与E2F2（其中E2F2特异性表达于神经元细胞）会在DNA损伤发生后被转录诱导。这种上调作用通过从头合成（de novo）蛋白质合成途径，提升E2F1与E2F2的蛋白水平。在神经元细胞中异位表达上述E2F家族成员，可降低遗传毒性处理后细胞的DNA损伤程度；而敲除E2F1与E2F2则会导致DNA损伤积累，并增强细胞的凋亡反应。E2F1与E2F2的缺失同样会降低细胞活力以及DNA损伤诱导后的DNA修复能力。最后，E2F1与E2F2会富集于氧化损伤与紫外线诱导的DNA损伤位点，并与γH2AX DNA修复因子（γH2AX DNA repair factor）发生相互作用。正如此前关于E2F1的研究报道所示，E2F2可促进Rad51灶点形成，与GCN5乙酰转移酶（GCN5 acetyltransferase）结合，并在遗传毒性应激诱导后引发组蛋白乙酰化。本研究结果揭示了一种全新的调控机制，即E2F1与E2F2可通过该机制在神经元细胞应答DNA损伤的过程中维持基因组稳定性。