December 4, 2010 | David F. Coppedge

Cells Manage Stress and Death

Like soldiers in a foreign land, cells sometimes find themselves in unexpected situations.  Key equipment breaks down, or the environment puts stress on their resources.  Without the ability to adapt, they could perish – and in worst-case scenarios they must, like a squadron under ambush with no way out.  In such cases, like spies carrying cyanide vials, cells commit orderly suicide for the good of the organism.  Two papers in Science describe how cells do it.
    DNA damage is like an emergency in the field.  Fortunately, cells have elaborate procedures for dealing with it, like a flowchart, where remaining resources adapt and fix the damage.  Israeli scientists Friedman and Schuldiner,1 summarizing a paper in the same issue of Science,2 described the “DNA Damage Road Map.”  Bandyopadhyay et al had “discovered widespread changes in genetic interaction among yeast kinases, phosphatases, and transcription factors as the cell responds to DNA damage.”  The technique they used was like turning still pictures into a movie: “Differential interactions uncover many gene functions that go undetected in static conditions.”  Notably, “The data also reveal that protein complexes are generally stable in response to perturbation, but the functional relations between these complexes are substantially reorganized.”
    Friedman and Schuldiner described how the team had put yeast cells under stress by adding methyl methanesulfonate, a DNA-damaging agent, and watched how they behaved differently from those in a stable environment.  The genetic networks reorganized themselves to handle the situation; “A bird’s-eye view of the dE-MAP reveals that protein complexes tended to remain stable across the two conditions,” they said.  “The relationships between these complexes, however, were reprogrammed to assist the cell in dealing with stress.”  For instance, a transcription factor affected “cell cycle checkpoints (which ensure the fidelity of cell division).”  Being able to see networks respond in sequence represents a new frontier in biochemistry, they said.  What’s more, “There are hundreds of such stories in the data.”
    Sometimes, when the stress is too great, death is the only option.  Every day in your body, millions of cells die due to stress, injury, infection, or “the natural cell turnover process that is essential to optimal tissue functioning.  That’s what Seamus J. Martin said in another Perspective piece in Science,3 describing how Ren et al, in the same issue,4 helped to resolve how cells execute the orderly process of cell suicide, called apoptosis.  “A cell must commit suicide at the appropriate time, otherwise malfunctioning or damaged cells could accumulate and lead to tumor development and other pathological conditions,” Martin said.  “Thus, sensors are needed to monitor the integrity of cellular functions and relay this information to the cell death machinery.”
    What Ren et al found is a “battery of sensors” that “detect cellular stress or damage through transcriptional or posttranslational mechanisms,” Martin said.  He described what happens when the suicide alarm sounds:

Upon activation, Bh3-only proteins provoke permeabilization of the mitochondrial outer membrane, allowing release of cytochrome c to the cytosol.  This efflux triggers assembly of the apoptosome, a structure that sets in motion a proteolytic cascade that coordinates cell death through destruction of hundreds of proteins (see the figure).  Because of their ability to unlock this cellular poison cabinet, Bh3-only proteins have come under intensive scrutiny.  How do these proteins provoke cytochrome c efflux?
    Bax and Bak, proteins that either reside in or insert into mitochondrial membranes, constitute the pore or channel that permeabilizes mitochondria.  Loss of Bax and Bak renders cells resistant to permeabilization (and subsequent apoptosis) caused by Bh3-only proteins.  Upon activation, Bh3-only proteins promote oligomerization of Bax and Bak within the mitochondrial outer membrane.  Thus, opening of the resultant channel effectively constitutes the decision to commit cellular suicide.

In other words, the sensors open the gates to prisoners who call the cellular council to assemble a death machine, which holds the keys to a poison cabinet.  During the process, a debate between pro-survival agents and death agents act like guards at the mitochondrial membrane checking one another’s credentials.  “Thus, Bh3-only proteins and prosurvival Bcl-2 proteins represent opposing forces in the struggle to control the channel, the outcome of which dictates whether a cell will live or die.”  A checking of codes in a nuclear weapons activation process comes to mind.  “Because of the deadly consequences of mitochondrial outer membrane permeabilization, this major checkpoint on the road to cell death is heavily policed,” Martin said.  When death is the only option remaining, it occurs in an orderly, systematic manner that leaves the rest of the organism at less risk.
    For more on apoptosis (programmed cell death), see 04/09/2002, 06/27/2003, 01/05/2006, 07/25/2006, 03/17/2007 and 08/14/2007.

1.  Nir Friedman and Maya Schuldiner, “Genetics: The DNA Damage Road Map,” Science, 3 December 2010: Vol. 330 no. 6009 pp. 1327-1328, DOI: 10.1126/science.1199862.
2.  Bandyopadhyay et al, “Rewiring of Genetic Networks in Response to DNA Damage,” Science, 3 December 2010: Vol. 330 no. 6009 pp. 1385-1389, DOI: 10.1126/science.1195618.
3.  Seamus J. Martin, “Cell Biology: Opening the Cellular Poison Cabinet,” Science, 3 December 2010: Vol. 330 no. 6009 pp. 1330-1331, DOI: 10.1126/science.1199461.
4.  Ren et al, “BID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK-Dependent Cell Death Program,” Science, 3 December 2010: Vol. 330 no. 6009 pp. 1390-1393, DOI: 10.1126/science.1190217.

Did you have any idea of the drama occurring inside your body millions of times a day?  Your cells are constantly struggling against real foes: genetic mistakes, toxins, environmental stress, injury, infection, and overcrowding.  Fortunately, there are elaborate policies and procedures, with police and programs, knowing how to handle each situation.  None of these papers said anything about evolution.  No wonder; this all sounds so much like intelligent design, it brings to mind images of cellular governments with documented foreign policy and homeland security systems.  And the first paper was talking about yeast cells!
    How on earth can anyone continue holding on to a doctrine like Darwinism that was concocted by a guru (02/15/2004 commentary) who knew nothing of what was happening in the little globs of protoplasm mischaracterized by the scientists of his day?  Martin talked about information being conveyed by these cellular agents, leading to decisions.  The other papers talked about whole networks of information adapting to change by adjusting their interactions – including assessing the extent of damage, accelerating or repressing gene translation, and striving to maintain stability in response to stress.  Only two things on earth we know of do that kind of thing: human minds, and robotic systems programmed by human minds.  But human minds did not program the cell.  What does that imply?  Think, now, those of you who consider yourselves heirs of the Age of Reason.

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