Not So Fast: Dividing Cells Use a “Speed Limit” to Avoid Genetic Mistakes

Pictured: Human cell nucleus

This image, generated in the lab of molecular biologist Prasad Jallepalli, shows a human cell nucleus — a membrane-enclosed compartment within a cell that contains DNA (in blue above). The red and green dots mark the rim of the nucleus.

One of the main functions of the nucleus is to protect the cell’s chromosomes, or DNA molecules, and preserve their genetic information when the cell divides. Errors in cell division can lead to the birth of new cells with abnormal sets of chromosomes, a phenomenon called aneuploidy. Normal cells have 46 chromosomes, but most cancer cells are aneuploid, containing one or several chromosomes too few or too many. In fact, aneuploidy is a sign that a cell’s growth and division is out of control.

Dr. Jallepalli and his colleagues have uncovered a previously unknown cellular mechanism that reduces the risk of aneuploidy. The discovery of this control mechanism — which Dr. Jallepalli describes as a kind of “cell division speed limit” — was recently reported in the journal Cell and could ultimately yield insights about the development of certain cancers.

Focus on Nuclear Pores

The findings extend scientists’ understanding of how cells normally maintain the integrity of their DNA and how the loss of this control may lead to cancer. Among other conclusions, the study revealed that nuclear pores — large protein structures that form openings in the membranes that encircle the cell nucleus — are important for the maintenance of genome integrity. In the image above, nuclear pores appear as red dots.

“The nuclear pore has a well-established role as a portal for molecules to move in and out of the nucleus,” Dr. Jallepalli says. “However, we discovered that this structure plays an additional role in setting the speed of cell division that wasn’t known before.”

The investigators found that a pair of proteins called Mad1 and Mad2 can attach to nuclear pores and send a signal within the cell to delay the onset of cell division. (The green dots in the image mark the location of Mad1 at nuclear pores.)

Stoplights and Speed Limits

“Like cars traveling on a road, our cells encounter both speed limits and stoplights to avoid genetic accidents,” Dr. Jallepalli explains.

The presence of a “stoplight” mechanism has been known for a long time and is part of a cellular process called the mitotic checkpoint. “Studies in many labs over the past ten to 15 years led to a more or less accepted picture of how this checkpoint works,” Dr. Jallepalli says. “In essence, chromosomes that are at risk of being gained or lost can send a type of distress signal to halt cell division until the underlying problem is fixed.”

The recent discovery of an additional signal emitted from the nuclear pores — the “speed limit” — suggests that there is also a more preemptive level of control in which a cell slows down its division to prevent genetic errors from arising in the first place.

“What makes this particularly interesting is the fact that some types of cancer, such as thyroid and stomach cancer, are associated with mutations that corrupt the speed-limit machinery,” Dr. Jallepalli notes. He and his coworkers are now exploring whether their findings might translate into better understanding of how such cancers develop or offer new ideas for how the diseases could be managed in the future.

This research was supported by the National Cancer Institute of the National Institutes of Health under award number R01GM077238 and R01GM094972 and by the G. Harold and Leila Y. Mathers Foundation, among other sources.