Nanoscale DNA slices reveal cell division force

U. MICHIGAN (US)—Biomedical engineers at the University of Michigan are using ultrafast laser pulses to slice off pieces of chromosomes to better understand genetic diseases, aging, and cancer.

Alan Hunt, an associate professor of biomedical engineering at Michigan, performed “nanoscale surgery,” as he calls it, taking advantage of the unprecedented precision of femtosecond pulses of laser light. A femtosecond is one billionth of one millionth of a second. The chromosomes he altered were only micrometers long, and the slices across the chromosomes were only nanometers thick. A nanometer is one-billionth of a meter, about a million times thinner than a human hair.

Cells in plants, fungi, and animals—including those in the human body—divide through mitosis, during which the DNA-containing chromosomes separate between the resulting daughter cells. Forces in a structure called the mitotic spindle guide the replicated chromosomes to opposing sides as one cell eventually becomes two.

“Each cell needs the right number of chromosomes. It’s central to life in general and very important in terms of disease,” says Hunt, author of a paper describing these findings published in Current Biology.

“One of the really important fundamental questions in biology is how do chromosomes get properly segregated when cells divide,” notes Hunt. “What are the forces that move chromosomes around during this process? Where do they come from and what guides the movements?”

Hunt’s work confirms the theory that polar ejection forces provide physical cues to guide chromosome movements and play a central role separating chromosomes in dividing cells.

Polar ejection forces are thought to arise out of the interaction between protein motors on the arms of chromosomes that push against cells’ microtubules—long, thin tubes that form a central component of the cytoskeleton and the mitotic spindle. They serve as intracellular structural supports and as railways along which molecular motors move cargoes such as chromosomes.

Hunt’s group hypothesized that polar ejection forces should be proportional to the chromosome’s size, and therefore could be predictably changed by altering the size of the chromosomes. Using newts as a model organism, they cut off pieces of the chromosomes’ arms.

“We asked what the relationship is between the size of the fragment we removed and the direction the chromosome moved,” explains Hunt. “Not only did we observe a relationship, we established that polar ejection forces were in fact a direct cue that guided chromosomal movements in mitosis.”

Understanding how chromosome guidance occurs allows scientists to determine how failures lead to disease. When cells don’t properly divide, they usually die, but if they survive, cancer, aging-related disorders, or genetic diseases like Down’s syndrome can result.

Mitosis, Hunt says, is one of the most important targets of chemotherapy.

“By knowing how chromosomes move, we can better understand how drugs interfere with those movements and we can design experiments to screen for new drugs,” Hunt says. “It will also allow us to have a better handle on what makes these drugs work. There are a lot of drugs that interfere with mitosis, but only a few are good for cancer therapy.”

This research is funded by the National Science Foundation, the National Institutes of Health, and the Cellular Biotechnology Training Grant at the University of Michigan.

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