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Hyper-activation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage.

Finzel, Ana and Grybowski, Andrea and Strasen, Jette and Cristiano, Elena and Loewer, Alexander (2016):
Hyper-activation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage.
In: Molecular biology of the cell, pp. 2360-2367, 27, (15), ISSN 1939-4586, [Article]

Abstract

A functional DNA damage response is essential for maintaining genome integrity in the presence of DNA double strand breaks. It is mainly coordinated by the kinases ATM, ATR and DNA-PKcs, which control the repair of broken DNA strands and relay the damage signal to the tumor suppressor p53 to induce cell cycle arrest, apoptosis or senescence. Although many functions of the individual kinases have been identified, it remains unclear how they act in concert to ensure faithful processing of the damage signal. Using specific inhibitors and quantitative analysis at the single cell level, we systematically characterize the contribution of each kinase for regulating p53 activity. Our results reveal a new regulatory interplay, where loss of DNA-PKcs function leads to hyper-activation of ATM and amplification of the p53 response, sensitizing cells for damage-induced senescence. This interplay determines the outcome of treatments regimens combining irradiation with DNA-PKcs inhibitors in a p53-dependent manner.

Item Type: Article
Erschienen: 2016
Creators: Finzel, Ana and Grybowski, Andrea and Strasen, Jette and Cristiano, Elena and Loewer, Alexander
Title: Hyper-activation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage.
Language: English
Abstract:

A functional DNA damage response is essential for maintaining genome integrity in the presence of DNA double strand breaks. It is mainly coordinated by the kinases ATM, ATR and DNA-PKcs, which control the repair of broken DNA strands and relay the damage signal to the tumor suppressor p53 to induce cell cycle arrest, apoptosis or senescence. Although many functions of the individual kinases have been identified, it remains unclear how they act in concert to ensure faithful processing of the damage signal. Using specific inhibitors and quantitative analysis at the single cell level, we systematically characterize the contribution of each kinase for regulating p53 activity. Our results reveal a new regulatory interplay, where loss of DNA-PKcs function leads to hyper-activation of ATM and amplification of the p53 response, sensitizing cells for damage-induced senescence. This interplay determines the outcome of treatments regimens combining irradiation with DNA-PKcs inhibitors in a p53-dependent manner.

Journal or Publication Title: Molecular biology of the cell
Volume: 27
Number: 15
Divisions: 10 Department of Biology
10 Department of Biology > Systems Biology of the Stress Response
Date Deposited: 14 Jun 2016 11:44
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