Repost: Controls are Cool

Many of you know that as a post-doc in Uri Alon’s lab, Galit Lahav caused a small revolution in our understanding of how the p53 network responds to DNA damage.  By looking at single cells instead of populations, she showed that individual cells responding to the damage caused by gamma-irradiation show a series of stereotyped pulses (shown in this movie); different cells show different numbers of pulses, and as you increase the amount of damage, the number of pulses per cell increases.  Now the Lahav lab has identified another previously unsuspected feature of the p53 response (Loewer A, Batchelor E, Gaglia G, Lahav G.  2010.  Basal Dynamics of p53 Reveal Transcriptionally Attenuated Pulses in Cycling Cells Cell 142 89-100. PMID: 20598361). It turns out that p53 is being activated in normal growing cells all the time.  Because the cell cycle of cells in culture is unsynchronized, this activation can only be seen by looking at single cells. Since p53 may be the most studied protein on the planet, discovering something completely new and unexpected about its activities isn’t an everyday event.

The story started with an experiment that was originally intended as a control, looking at unstressed cells.  Unexpectedly, in these unstressed, undamaged cells they found p53 pulses that are indistinguishable in shape from the pulses seen in gamma-irradiated cells. The first clue to where these pulses come from was the observation that they’re correlated with specific stages of the cell cycle, primarily happening right after mitosis.  Loewer et al. used a Cdk inhibitor to show that when the cell cycle is stopped, the pulses go away.  And the pulses were also selectively stopped when the ATM/DNA-PK pathway, which monitors double-stranded DNA breaks, was inhibited. It appears that these pulses are triggered by transient DNA damage that is a routine part of the cell cycle.

Synthetic probes of natural oscillations

One of the motivations for systems biology is the gathering realization that biological systems are not simply composed of on/off switches.  Instead of thinking of signal transduction as a simple relay race — A passes the information to B, who passes it to C — we need to understand the information processing in multiple layers of feedback and feed-forward loops.  The dynamics of the components of the pathway are our best window onto the behaviors of these loops.  But the complexity of natural systems is such that interpreting protein dynamics is often not easy.  The Lahav lab has been chewing away at one such problem for a while: the dynamics of the transcription factor p53, one of the body’s most important defenses against cancer. After DNA damage, the p53 network is responsible for making the decision of whether the cell should arrest the cell cycle and attempt to repair the damage, carry on, or die.  Most cancer cells have lost the ability to choose correctly when faced with this situation.

Controls are cool

Many of you know that as a post-doc in Uri Alon’s lab, Galit Lahav caused a small revolution in our understanding of how the p53 network responds to DNA damage.  By looking at single cells instead of populations, she showed that individual cells responding to the damage caused by gamma-irradiation show a series of stereotyped pulses (shown in this movie); different cells show different numbers of pulses, and as you increase the amount of damage, the number of pulses per cell increases.  Now the Lahav lab has identified another previously unsuspected feature of the p53 response (Loewer A, Batchelor E, Gaglia G, Lahav G.  2010.  Basal Dynamics of p53 Reveal Transcriptionally Attenuated Pulses in Cycling Cells Cell 142 89-100. PMID: 20598361). It turns out that p53 is being activated in normal growing cells all the time.  Because the cell cycle of cells in culture is unsynchronized, this activation can only be seen by looking at single cells. Since p53 may be the most studied protein on the planet, discovering something completely new and unexpected about its activities isn’t an everyday event.

The story started with an experiment that was originally intended as a control, looking at unstressed cells.  Unexpectedly, in these unstressed, undamaged cells they found p53 pulses that are indistinguishable in shape from the pulses seen in gamma-irradiated cells. The first clue to where these pulses come from was the observation that they’re correlated with specific stages of the cell cycle, primarily happening right after mitosis.  Loewer et al. used a Cdk inhibitor to show that when the cell cycle is stopped, the pulses go away.  And the pulses were also selectively stopped when the ATM/DNA-PK pathway, which monitors double-stranded DNA breaks, was inhibited. It appears that these pulses are triggered by transient DNA damage that is a routine part of the cell cycle.