*Study reveals previously unknown roles for conserved protein complexes in the cell division process.*
February 24, 2023
Berkeley, CA—A team of scientists led by researchers at the University of California, Berkeley, has discovered a new mechanism that cells use to ensure the even distribution of genetic material during cell division. The finding, published in the journal *Nature*, challenges the long-standing model of how this critical cellular process occurs and could have implications for understanding and treating diseases caused by mistakes in chromosome segregation, such as Down syndrome and certain cancers.
During cell division, a cell must precisely duplicate and then distribute its chromosomes—structures that carry the cell’s genetic information—into two new cells. The cell uses a complex machinery of proteins to ensure that each new cell ends up with the correct complement of chromosomes, but exactly how this machinery operates remains a subject of intense scientific study.
The prevailing theory, known as the “kinetochore-tension” model, has held that specialized protein complexes called kinetochores, which form on the surface of the chromosomes, sense and respond to forces generated during chromosome segregation. Like tug-of-war teams balancing their grip on a rope, these kinetochores would exert forces on the chromosomes until the forces were balanced, indicating that the chromosomes were properly aligned and ready to be divided.
In their new study, the Berkeley-led team discovered that while the kinetochores are indeed important, an entirely different set of protein complexes, called the chromosomal passenger complexes (CPCs), are also critical to monitoring and correcting mistakes in chromosome distribution. The researchers made this discovery by developing a new method to study cell division in the three-dimensional space of a living organism.
“Kinetochores were known to be important, but we were surprised to find that the passenger proteins are also essential for sensing errors in chromosome segregation. Our work changes the paradigm of how we think about this fundamental cellular process,” said lead author Ashley Pagliuca, a UC Berkeley postdoctoral researcher.
Using their new imaging method, the researchers tracked the movements of CPCs as they interacted with chromosomes during mitosis, the process by which a cell divides into two identical daughter cells. To their surprise, they found that the CPCs were not only constantly in motion, but also highly dynamic, constantly changing their shape and composition as they moved along the chromosomes. This dynamic behavior allowed the CPCs to sample the forces being generated by the kinetochores and to identify when chromosomes were not properly aligned.
“The CPCs were literally acting like cellular hands, moving back and forth along the chromosome arms until they could reach out and grab onto microtubules, which are tiny filaments that help to pull chromosomes apart,” said co-senior author Rebecca Heald, a UC Berkeley professor of molecular and cell biology. “They would then pull on these microtubules and move chromosomes around, correcting errors in chromosome alignment.”
In follow-up experiments, the researchers were able to demonstrate that CPCs were essential for the accurate segregation of chromosomes during cell division. When they depleted CPCs from cells, the cells frequently made mistakes in chromosome distribution, resulting in aneuploidy—a condition in which cells have an abnormal number of chromosomes. These results suggest that CPCs play a critical role in preventing aneuploidy, which can lead to developmental defects, miscarriages, and certain types of cancer.
“Our discovery opens up new avenues for understanding the causes of aneuploidy and for developing potential therapies for diseases associated with aneuploidy,” said Pagliuca.
The research was supported by the National Institutes of Health, the National Science Foundation, the UCSF Cancer Center, and the Jane Coffin Childs Memorial Fund for Medical Research.
