How cells correct errors under time pressure
Cells go through a life cycle that includes growing to the right size, being equipped to perform its functions, and finally dividing into two new cells. The cell cycle is critical because it ensures the perpetuation of the cell population and by extension of the greater structure they are a part of — for example a tissue in the body.
The cell cycle itself is tightly regulated by checkpoints, which prevent errors like mutations or DNA damage from being passed onto the next generation of cells. Each checkpoint acts as a kind of quality-control monitor (a biological “checklist”) that ensures the order, integrity, and fidelity of the cell cycle. But checkpoints themselves often fail or are overridden after a prolonged stop of the cell cycle. If this happens in the human body, the result could be unregulated cell growth and division, which is what happens in cancer.
“Checkpoints monitor cells or whole organisms and can stop either the cell cycle or the organism’s development when they detect problems,” says Sahand Jamal Rahi at EPFL’s School of Basic Sciences. “But if cells or organisms are stuck with an error for a very long time, in many cases, they just continue dividing or growing; they don’t stop forever. There is a real risk of dying if checkpoints do not stop at all, but also waiting forever is effectively equivalent to dying.”
The math of checkpoint override
The question is then, how does the cell balance risk and speed when dividing? Although critical, checkpoint override is not very well understood, neither theoretically nor experimentally. But in a new paper, Rahi and his colleagues put forward the first mathematical theory to describe the process of checkpoint override. “Many organisms have to predict what’s going to happen,” he says. “You have a problem and you have to assess how bad that problem could be because the consequences are not certain. You could survive this or you might not survive this. So, the cell makes a bet either way. And in this study, we analyze the odds of that bet.”
For a real-life model organism, the researchers looked at the budding yeast Saccharomyces cerevisiae, which has been used in winemaking, baking and brewing for centuries. “There are systems that monitor organisms, and among these systems, possibly the best studied is the DNA damage checkpoint in yeast,” says Rahi. “So, we thought, let’s look at that and see whether we can make sense of checkpoint overrides. We started with a mathematical analysis behind which was a very simple question: what if these organisms are balancing risk and speed because they have to predict the future?”
The risk-speed tradeoff More