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Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage.

Batchelor, Eric and Mock, Caroline S. and Bhan, Irun and Loewer, Alexander and Lahav, Galit (2008):
Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage.
In: Molecular cell, 30 (3), pp. 277-89. ISSN 1097-4164,
[Article]

Abstract

DNA damage initiates a series of p53 pulses. Although much is known about the interactions surrounding p53, little is known about which interactions contribute to p53's dynamical behavior. The simplest explanation is that these pulses are oscillations intrinsic to the p53/Mdm2 negative feedback loop. Here we present evidence that this simple mechanism is insufficient to explain p53 pulses; we show that p53 pulses are externally driven by pulses in the upstream signaling kinases, ATM and Chk2, and that the negative feedback between p53 and ATM, via Wip1, is essential for maintaining the uniform shape of p53 pulses. We propose that p53 pulses result from repeated initiation by ATM, which is reactivated by persistent DNA damage. Our study emphasizes the importance of collecting quantitative dynamic information at high temporal resolution for understanding the regulation of signaling pathways and opens new ways to manipulate p53 pulses to ask questions about their function in response to DNA damage.

Item Type: Article
Erschienen: 2008
Creators: Batchelor, Eric and Mock, Caroline S. and Bhan, Irun and Loewer, Alexander and Lahav, Galit
Title: Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage.
Language: English
Abstract:

DNA damage initiates a series of p53 pulses. Although much is known about the interactions surrounding p53, little is known about which interactions contribute to p53's dynamical behavior. The simplest explanation is that these pulses are oscillations intrinsic to the p53/Mdm2 negative feedback loop. Here we present evidence that this simple mechanism is insufficient to explain p53 pulses; we show that p53 pulses are externally driven by pulses in the upstream signaling kinases, ATM and Chk2, and that the negative feedback between p53 and ATM, via Wip1, is essential for maintaining the uniform shape of p53 pulses. We propose that p53 pulses result from repeated initiation by ATM, which is reactivated by persistent DNA damage. Our study emphasizes the importance of collecting quantitative dynamic information at high temporal resolution for understanding the regulation of signaling pathways and opens new ways to manipulate p53 pulses to ask questions about their function in response to DNA damage.

Journal or Publication Title: Molecular cell
Journal volume: 30
Number: 3
Divisions: 10 Department of Biology
10 Department of Biology > Systems Biology of the Stress Response
Date Deposited: 02 Sep 2015 08:59
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