title: E2F1 and E2F2 induction in response to DNA damage preserves genomic stability in neuronal cells.
abstract: 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 E2F1 and E2F2, 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 de novo 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.
authors.affiliation: a Laboratorio de Biología Molecular; Departamento de Química Biológica; Facultad de Ciencias Exactas y Naturales ; Universidad de Buenos Aires ; Ciudad de Buenos Aires , Argentina.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Castillo
authors.forename: Anna
authors.initials: A
authors.lastname: Campalans
authors.forename: Laura M
authors.initials: LM
authors.lastname: Belluscio
authors.forename: Abel L
authors.initials: AL
authors.lastname: Carcagno
authors.forename: J Pablo
authors.initials: JP
authors.lastname: Radicella
authors.forename: Eduardo T
authors.initials: ET
authors.lastname: Cánepa
authors.forename: Nicolás
authors.initials: N
authors.lastname: Pregi
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003513:Cycloheximide / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects; D003609:Dactinomycin / Q000633:toxicity; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050703:E2F2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability / Q000187:drug effects / Q000528:radiation effects; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000633:toxicity; D051135:Rad51 Recombinase / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D003513:Cycloheximide; D003609:Dactinomycin; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D006657:Histones; D006861:Hydrogen Peroxide; D020930:MAP Kinase Kinase Kinases; D011500:Protein Synthesis Inhibitors; D051135:Rad51 Recombinase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C468783:H2AX protein, human
keywords: ASCAT, CAT antisense; ASE2F1, E2F1 antisense; ASE2F2, E2F2 antisense; DNA damage response; DNA repair; E2F transcription factor; NCS, neocarzinostatin; ODN, oligodeoxynucleotide; genomic stability; mut E2F DO, mutant E2F decoy oligodeoxynucleotide; neuronal cells; wt E2F DO, wild-type E2F decoy oligodeoxynucleotide