Scientists from the Hutchinson Center, University of Washington and Institute for Systems Biology have discovered an amazingly simple way that cells stabilize their machinery for forcing apart chromosomes. When a cell gets ready to split into new cells, this steady setup permits its genetic material to be separated and distributed accurately. Otherwise, problem cells—like cancer cells—arise. The findings are reported Nov. 25 in Nature.
The human body contains more than a trillion cells, and every single cell needs to have the exact same set of chromosomes. Mistakes in moving chromosomes during cell division can lead to babies being born with genetic conditions like Down syndrome, where cells have an extra copy of chromosome 21.
"A striking hallmark of cancer cells is that they contain the wrong number of chromosomes, so it is essential that that we understand how chromosome separation is controlled," said the Basic Sciences Division's Dr. Sue Biggins, one of the senior authors of the study. "This knowledge could potentially lead to ways to correct defects before they occur, or allow us to try to target cells with the wrong number of chromosomes to prevent them from dividing again."
First-time isolation of movement mechanism
Kinetochores, mechanisms inside cells that move the chromosomes, appear on the chromosomes and attach to dynamic filaments during cell division. Kinetochores drive chromosome movement by keeping a grip on the filaments, which are constantly remodeling. The growth and shortening of the filaments tugs on the kinetochores and chromosomes until they separate.
"The kinetochore is one of the largest cellular machines but had never been isolated before,” Biggins said. "Our labs isolated these machines for the first time. This allowed us to analyze their behavior outside of the cell and find out how they control movement."
"We demonstrated that attachments between kinetochores and microtubule filaments become more stable when they are placed under tension," said Dr. Charles "Chip" Asbury, a UW associate professor of physiology and biophysics and another senior author on the paper.
Asbury likened the stabilizing tension on the filament to a Chinese finger trap toy—the harder you try to pull away, the stronger your knuckles are gripped.
He said this tension-dependent stabilization helps chromosomes separate according to plan. As cell division approaches, a mitotic spindle forms. When chromosome pairs are properly connected to the spindle, the kinetochore comes under mechanical tension and the attachment becomes stabilized, sort of like steadying a load by tightening ropes on either side.
"On the other hand, if the chromosome pair is not properly attached, the kinetochores do not come under full tension," Asbury said. "The attachments are unstable and release quickly, giving another chance for proper connections to form," making kinetochores not just connectors, but regulatory hubs. They sense and fix errors in attachment and emit “wait” signals until the microtubule filaments are in the right place.
The results of this study contribute to wider efforts to understand the phenomenon of how motion and force are produced to move duplicated chromosomes apart before cells divide.
Center authors included graduate student Hugo Arellano-Santoyo of the joint Center/UW Molecular and Cellular Biology program and two former Center employees, graduate student Bungo Akiyoshi and research technician Christian Nelson.
The research was funded by grants from the National Institute of General Science at the National Institutes of Health, the Packard Foundation, the Kinship Foundation and the Beckman Foundation.
[Adapted from a University of Washington news release]