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

Eric Batchelor — 2008-05-09T11:43:28-00:00

Molecular Cell, Vol. 30, No. 3. (9 May 2008), pp. 277-289.

Summary 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.

Colocalization of Sensors Is Sufficient to Activate the DNA Damage Checkpoint in the Absence of Damage

Carla Bonilla — 2008-05-09T11:40:24-00:00

Molecular Cell, Vol. 30, No. 3. (9 May 2008), pp. 267-276.

Summary Previous work on the DNA damage checkpoint in Saccharomyces cerevisiae has shown that two complexes independently sense DNA lesions: the kinase Mec1-Ddc2 and the PCNA-like 9-1-1 complex. To test whether colocalization of these components is sufficient for checkpoint activation, we fused these checkpoint proteins to the LacI repressor and artificially colocalized these fusions by expressing them in cells harboring Lac operator arrays. We observed Rad53 and Rad9 phosphorylation, Sml1 degradation, and metaphase delay, demonstrating that colocalization of these sensors is sufficient to activate the checkpoint in the absence of DNA damage. Our tethering system allowed us to establish that CDK functions in the checkpoint pathway downstream of damage processing and checkpoint protein recruitment. This CDK dependence is likely, at least in part, through Rad9, since mutation of CDK consensus sites compromised its checkpoint function.

CiteULike: renatomilani dna-damage

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

Colocalization of Sensors Is Sufficient to Activate the DNA Damage Checkpoint in the Absence of Damage