title: E2F1 induces p19INK4d, a protein involved in the DNA damage response, following UV irradiation.
abstract: Central to the maintenance of genomic integrity is the cellular DNA damage response. Depending on the type of genotoxic stress and through the activation of multiple signaling cascades, it can lead to cell cycle arrest, DNA repair, senescence, and apoptosis. p19INK4d, a member of the INK4 family of CDK inhibitors, plays a dual role in the DNA damage response, inhibiting cell proliferation and promoting DNA repair. Consistently, p19INK4d has been reported to become upregulated in response to UV irradiation and a great variety of genotoxic agents. Here, this induction is shown to result from a transcriptional stimulatory mechanism that can occur at every phase of the cell cycle except during mitosis. Moreover, evidence is presented that demonstrates that E2F1 is involved in the induction of p19INK4d following UV treatment, as it is prevented by E2F1 protein ablation and DNA-binding inhibition. Specific inhibition of this regulation using triplex-forming oligonucleotides that target the E2F response elements present in the p19INK4d promoter also block p19INK4d upregulation and sensitize cells to DNA damage. These results constitute the first description of a mechanism for the induction of p19INK4d in response to UV irradiation and demonstrate the physiological relevance of this regulation following DNA damage.
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria Pabellón II Piso 4, 1428, Ciudad de Buenos Aires, Argentina. abelc@qb.fcen.uba.ar
authors.forename: Abel L
authors.initials: AL
authors.lastname: Carcagno
authors.forename: Luciana E
authors.initials: LE
authors.lastname: Giono
authors.forename: Mariela C
authors.initials: MC
authors.lastname: Marazita
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Castillo
authors.forename: Nicolás
authors.initials: N
authors.lastname: Pregi
authors.forename: Eduardo T
authors.initials: ET
authors.lastname: Cánepa
mesh_terms: D000818:Animals; D002453:Cell Cycle; D006224:Cricetinae; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D020218:Response Elements; D014158:Transcription, Genetic / Q000528:radiation effects; D015533:Transcriptional Activation / Q000528:radiation effects*; D014466:Ultraviolet Rays
chemical_list: D050764:Cyclin-Dependent Kinase Inhibitor p19; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C051802:triplex DNA; D004247:DNA