Sending out an SOS: How telomeres incriminate cells that can't divide
The well-being of living cells requires specialized squads of proteins that maintain order, chewing up worn-out proteins, wrapping up damaged organelles, and—most importantly—repairing anything that resembles a broken chromosome. If repair is impossible, the crew foreman calls in executioners to annihilate a cell. As unsavory as this last bunch sounds, failure to summon them is one aspect of what makes a cancer cell a cancer cell.
A recent study by scientists in the lab of Jan Karlseder showed exactly how cells sense the possibility that their DNA is damaged as a first step to responding to the failure to divide properly. The study, published in Nature Structural and Molecular Biology, found that if cells take too long to undergo cell division, protective structures at the tips of their chromosomes, known as telomeres, send out a molecular SOS. The findings have dual implications for cancer chemotherapy. First, they show how a class of anti-cancer drugs that slows cell division—known as mitotic inhibitors—kills cells. More significantly, the findings suggest ways to make therapy with those inhibitors more potent.
Initially, the group searched for specific proteins that might keep telomeres intact during cell division. What they found was unexpected— that any manipulation that crippled and prolonged cell division produced increased numbers of telomere blobs indicative of "unprotected" telomeres. Moreover, treating cells with mitotic inhibitors used in cancer chemotherapy did the very same thing. Those studies established a link between arrested mitosis, telomere perturbation and cell death. Karlseder's group then confirmed that as cells stalled in mitosis, telomeres started to disintegrate.
This work suggests novel strategies that could be used in combinatorial cancer chemotherapy regimes, which rely on the synergy between two or more drugs.
"To make therapy more effective and reduce side effects, we might be able to use more moderate levels of mitotic inhibitors, which at high doses can cause severe side effects, paired with a different drug that sensitizes cells to the DNA damage response," says Karlseder. "That could improve the chances of catching 100 percent of the tumor cells."