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Differential regulation of E2F1 apoptotic target genes in response to DNA damage
Natalia Pediconi1, Alessandra Ianari, Antonio Costanzo
1Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome La Sapienza, Viale del Policlinico 155, 00161 Rome, Italy.
Abstract:
E2F1, a member of the E2F family of transcription factors, in addition to its established proliferative effect, has also been implicated in the induction of apoptosis through p53-dependent and p53-independent pathways. Several genes involved in the activation or execution of the apoptotic programme have recently been shown to be upregulated at the transcriptional level by E2F1 overexpression, including the genes encoding INK4a/ARF, Apaf-1, caspase 7 and p73 (refs 3-5). E2F1 is stabilized in response to DNA damage but it has not been established how this translates into the activation of specific subsets of E2F target genes. Here, we applied a chromatin immunoprecipitation approach to show that, in response to DNA damage, E2F1 is directed from cell cycle progression to apoptotic E2F target genes. We identify p73 as an important E2F1 apoptotic target gene in DNA damage response and we show that acetylation is required for E2F1 recruitment on the P1p73 promoter and for its transcriptional activation.
Insights
E2F1 transcription factor shifts from cell cycle to apoptosis genes after DNA damage. Acetylation is crucial for E2F1 binding to the p73 gene promoter, activating apoptosis.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- E2F1 transcription factor regulates cell proliferation and apoptosis.
- E2F1 overexpression upregulates apoptotic genes like INK4a/ARF, Apaf-1, caspase 7, and p73.
- The mechanism of E2F1 target gene activation following DNA damage is unclear.
Purpose of the Study:
- To investigate how E2F1 is redirected to apoptotic genes upon DNA damage.
- To identify key E2F1 apoptotic target genes involved in DNA damage response.
- To elucidate the role of post-translational modifications in E2F1-mediated gene activation.
Main Methods:
- Chromatin immunoprecipitation (ChIP) to analyze E2F1 binding to target gene promoters.
- Analysis of gene expression changes in response to DNA damage.
- Investigating the role of protein acetylation in E2F1 recruitment and transcriptional activity.
Main Results:
- In response to DNA damage, E2F1 is recruited to apoptotic target genes, away from cell cycle genes.
- p73 is identified as a critical E2F1 apoptotic target gene in the DNA damage response.
- Acetylation of E2F1 is essential for its binding to the P1p73 promoter and subsequent transcriptional activation.
Conclusions:
- E2F1 plays a dual role in cell cycle progression and apoptosis, with a shift towards apoptosis induction upon DNA damage.
- p73 is a key mediator of E2F1's pro-apoptotic function in DNA damage response.
- Acetylation is a critical regulatory mechanism controlling E2F1's function in apoptosis.