November 16, 2003
La Jolla, CA – Salk Institute scientists have for the first time linked the function of a group of proteins required for DNA duplication and accurate chromosome movement during cell division. The findings may help explain the genetic influences behind some forms of cancer.
The study, published in the December issue of Nature Cell Biology, identified a novel regulatory link between proteins required for duplication of genetic material, and proteins required for chromosome segregation to two new cells. Mutations of all these proteins have been found in cancer cells, and understanding how these proteins work may open the door to a new understanding of cancer.
Susan Forsburg, Salk associate professor of molecular and cell biology, Salk postdoctoral researcher Julie Bailis, and colleagues in Scotland and France found that proteins regulating the copying of DNA that must occur before cell division also regulated the cell’s later reproductive steps – the separation of chromosomes into newly created “daughter” cells.
“We found that proper regulation of genetic information is all about timing,” Forsburg said. “The same molecular mechanism that activates DNA synthesis also regulates the precise assembly of proteins and DNA into specialized chromosome structures called centromeres, required for chromosome separation later in cell division. Both these processes are important for normal cells, and both can go awry in cancer. This work shows us that the processes are linked, even though they occur at different times during cell division.”
Studying a form of yeast that was first isolated in East African beer, Forsburg and her team found that proper DNA synthesis and assembly of centromeres are linked by a regulatory protein called the Hsk1/Cdc7 kinase, and its partner Dfp1. Hsk1 and Dfp1 were known to regulate the synthesis of DNA, the first step in the process of cellular reproduction.
However, the scientists discovered that some defects in Hsk1/Dfp1’s function resulted in “lagging chromosomes,” which are chromosomes that are unable to migrate as they should to newly produced cells due to defects in their centromeres. The scientists concluded that Hsk also was involved in assembling the centromeres, which are required for the migration of chromosomes.
The group is now looking at other molecular interactions that may help ensure the accurate inheritance of genetic material in cells. The study was supported by grants from the American Cancer Society, the Damon Runyon Cancer Research Foundation, the Wellcome Trust, the French Centre National de la Recherche Scientifique, and the Leukemia and Lymphoma Society.
Forsburg and Bailis’ colleagues in the study include Pascal Bernard of CNRS, Bordeaux, France, and Richard Antonelli and Robin Allshire of the University of Edinburgh, Scotland.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.