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Published on: February 6, 2015
Activation of a Tip60/E2F1/ERCC1 network in human lung adenocarcinoma cells exposed to cisplatin
Arnaud Van Den Broeck1, Damien Nissou, Elisabeth Brambilla
1Equipe Bases Moléculaires de la Progression des Cancers du Poumon, Centre de Recherche INSERM U823, Institut Albert Bonniot BP170, 38042 Grenoble Cedex 09, France.
Abstract:
The Tip60 and E2F1 proteins are key players of the cellular response induced by genotoxic stresses. Here, new insights into the involvement of both proteins during the DNA damage response are provided. We show that Tip60 interacts with E2F1 and promotes its acetylation. We identify the lysine residues 120/125 of the E2F1 protein as the prime target sites of Tip60 and show that acetylation at these sites promotes the accumulation of E2F1. Importantly, we demonstrate that cisplatin induces the accumulation of E2F1 in a Tip60-dependent manner. However, and in contrast to PCAF and p300, Tip60 is not required for the induction of apoptosis in cisplatin-treated cells. Instead, Tip60 and E2F1 are involved in the upregulation of the excision repair cross-complementation group 1 protein expression, an enzyme involved in the repair of cisplatin-induced DNA lesions. These findings identify Tip60 as a direct regulator of E2F1 and support their cooperative role in DNA repair.
Insights
Tip60 protein directly regulates E2F1 protein by promoting its acetylation, which is crucial for DNA damage response. This interaction is vital for DNA repair, not apoptosis, in cells treated with genotoxic stress.
Area of Science:
- Molecular Biology
- Cellular Biology
- Genetics
Background:
- Tip60 and E2F1 proteins are critical in cellular responses to genotoxic stresses.
- Understanding their precise roles in DNA damage response is essential.
Purpose of the Study:
- To elucidate the interaction between Tip60 and E2F1 during DNA damage response.
- To investigate the role of Tip60-mediated E2F1 acetylation in cellular processes.
Main Methods:
- Co-immunoprecipitation assays to detect protein interactions.
- Mass spectrometry to identify acetylation sites.
- Western blotting to assess protein accumulation and expression.
- Cell viability assays to evaluate apoptosis induction.
Main Results:
- Tip60 directly interacts with and acetylates E2F1 at lysine residues 120/125.
- Acetylation promotes E2F1 accumulation in a Tip60-dependent manner following cisplatin treatment.
- Tip60 is not required for cisplatin-induced apoptosis but upregulates excision repair cross-complementation group 1 (XPG) expression.
- Tip60 and E2F1 cooperate in the upregulation of XPG, an enzyme involved in DNA repair.
Conclusions:
- Tip60 is a direct regulator of E2F1 acetylation and accumulation.
- Tip60 and E2F1 play a cooperative role in DNA repair pathways, specifically in response to cisplatin-induced DNA damage.
- Tip60's function in DNA damage response is distinct from its role in apoptosis induction.
