Silencing Proteins for Chromosome Copying
Researchers in Lawrence Berkeley National Laboratory’s (One Cyclotron Rd. Berkeley, CA 94720; Tel: 510/486-6467, Fax: 510/4865/6457) Life Sciences Division, led by Paul Kauffman, have discovered that two yeast proteins, previously known for helping to construct “silent” regions of chromosomes, also play a role chromosome segregation. The results are reported in the January 1, 2002 issue of Genes & Development.
“When cells divide, they must make sure that both daughter cells receive exactly one copy of each chromosome,” says Kaufman, a staff scientist at Berkeley Lab. “This process is known as chromosome segregation, and if it goes awry, cells can lose chromosomes or acquire more than one chromosome copy.” In humans, lack of a chromosome can cause blood disorders including leukemia; an extra chromosome 21 causes Down Syndrome.
As cell division begins, spindles form that will eventually pull the original chromosomes and their copies apart into two daughter cells. These spindles attach to constricted regions of chromosomes called centromeres: complexes of proteins called kinetochores fasten the centromeres to the spindles.
Kauffman and colleagues looked at two kinds of proteins known to be important for depositing proteins onto chromosomes. One, CAF-I (for Chromatin Assembly Factor I), puts together nucleosomes, the fundamental sub-units of chromosomes. Nucleosomes consist of DNA wrapped around groups of structural proteins called histones.
Kaufman’s lab had previously demonstrated that CAF-I and another set of proteins, called Hir (for histone regulatory), are important for the formation of so-called “silenced” regions of chromosomes, where large stretches of DNA are enveloped in protein structures that repress gene expression. Silencing is vital to chromosome stability and accurate segregation. In higher organisms, loss of silencing can lead to cancer; even in yeast it can lead to developmental abnormalities and premature aging.
When the researchers removed the genes that code for both CAF-I and Hir proteins, the growth rate of the yeast slowed markedly. Moreover, yeast lacking these genes lost chromosomes or gained extra ones hundreds of times more often than ordinary wild yeast. Yeast that lacked only one of the two genes was not similarly affected, however.
The delay in cell division that occurred when both genes were missing seemed due to the activation of the “spindle assembly checkpoint,” a mechanism that monitors the proper attachment of chromosomes to spindles before separation begins. This clue pointed to the involvement of kinetochores.
CAF-I and Hir proteins were shown to be highly localized on centromeres and therefore to act directly to affect structures at these locations. Their functions seem to overlap; thus they can partially substitute for each other if one is missing. But when both are missing, defects in centromere structures occur.
“This the first demonstration that proteins that control histone deposition contribute to the formation of functional kinetochores,” Kaufman says. “Kinetochores are essential to proper chromosome segregation during the cell division process.”
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