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

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

Research output: Contribution to journalArticlepeer-review

345 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)277-289
Number of pages13
JournalMolecular Cell
Issue number3
StatePublished - May 9 2008
Externally publishedYes

Bibliographical note

Funding Information:
We thank Uri Alon for encouragement and discussion; and Tim Mitchison, Roy Kishony, Ron Milo, Michael Springer, Shalev Itzkovitz, Nitzan Rosenfeld, Bodo Stern, Rebecca Ward, and all members of our laboratory for comments and discussions. We thank the Nikon Imaging Center at Harvard Medical School for assistance with immunofluorescence microscopy. This research was supported by the Smith Family New Investigator Awards Program (The Medical Foundation), the Giovanni Armenise-Harvard Foundation, and National Institutes of Health (NIH) grant GM083303. E.B. was partially supported by the American Cancer Society, California Division Pamela and Ed Taft Postdoctoral Fellowship. I.B. was supported by fellowships from Aid for Cancer Research and from the Howard Hughes Medical Institute.




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