Recurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage

Batchelor, Eric; Mock, Caroline S.; Bhan, Irun; Loewer, Alexander; Lahav, Galit

doi:10.1016/j.molcel.2008.03.016

Cited by 422Cancer-related Molecular PathwaysDNA Repair MechanismsGene Regulatory Network Analysis

Recurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage

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Batchelor, Eric, Mock, Caroline S., Bhan, Irun, Loewer, Alexander, Lahav, Galit·2008·Molecular Cell

DOI 10.1016/j.molcel.2008.03.016PMC PMC2579769

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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.

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DNA damage initiates a series of p53 pulses that ultimately lead to target gene activation.
“DNA damage, for example, initiates a series of p53 pulses that ultimately lead to target gene activation.57”
From Census and evaluation of p53 target genes (2017) · cites this paper as [57]

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Authors: Batchelor, E., Mock, C. S., Bhan, I., Loewer, A., & Lahav, G.
Affiliations: Harvard University (US)
Corresponding author: Lahav, Galit
ORCID: Batchelor, Eric
Bhan, Irun
Loewer, Alexander
Lahav, Galit
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2008-05
Volume: 30
Issue: 3
Pages: 277-289
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2008.03.016
PMC: PMC2579769
OpenAlex: W2010114834
Semantic Scholar: 2ffd69376efd29185361373d53cf740f372c24ee
Cited by: 422
References: 51
Citations by year: 2026: 10 · 2025: 20 · 2024: 12 · 2023: 12 · 2022: 22 · 2021: 24 · 2020: 21 · 2019: 31 · 2018: 20 · 2017: 29 · 2016: 19 · 2015: 27 · 2014: 30 · 2013: 32 · 2012: 29
FWCI: 14.78
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1903 d)
Locations: Molecular Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
American Cancer Society
National Institute of General Medical Sciences (R01GM083303, GM083303)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords: DNA damage response, ATM kinase, Chk2, Wip1, p53 oscillations, persistent DNA damage
MeSH terms: Protein Phosphatase 2C, Animals, DNA Damage, DNA-Binding Proteins, Gamma Rays, Humans, Imidazoles, Mathematics, Models, Theoretical, Phosphoprotein Phosphatases, Piperazines, Signal Transduction, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, RNA Interference, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2

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Recurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage

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