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Every cell in the body arises from the process of cell division—an intricate molecular process in which a cell precisely copies its gene-containing chromosomes and segregates them into identical parcels that migrate into the two new daughter cells. Malfunction of this segregation machinery can have profound consequences. In pregnancy, most miscarriages are caused by errors in this chromosomal process, which leaves daughter cells with an incorrect number of chromosomes. In addition, most solid tumors exhibit abnormal chromosomal segregation, which can deprive cells of chromosomes and leave them without the proper dosage of critical genes that act as safety brakes on cell division.
The action point in regulating chromosomal segregation is called the centromere. It is the centromere on which the critical machinery for governing segregation is assembled.
Janet Partridge, PhD, Biochemistry, and her colleagues are probing the details of this centromeric machinery using the yeast strain called S. pombe. Besides being simple to grow and genetically manipulate, the modest yeast makes an excellent experimental model because it has centromeres that are surprisingly complex like those of humans and other mammals.
In their latest work, the researchers have added a significant piece to the biological puzzle that is the centromeric machinery. The scientists published their findings in the April 9 issue of the journal Molecular Cell.
The study concentrates on understanding material called heterochromatin that assembles on centromeric sequences. This heterochromatin is a special form of the chromatin that packages all chromosomes. Such chromatin consists not only of DNA, but also of packaging proteins called histones that surround and protect the DNA. These histones are the smart packaging of chromatin because they undergo modifications that control recruitment of additional proteins and regulate how the genes are activated.
The investigators discovered a key molecular connection that enables a chunk of control machinery, called the RITS complex, to attach itself to a target histone that bears a specific modification, methylation of lysine 9 in histone H3, which is prevalent in heterochromatin. RITS carries gene-regulating molecules that govern the correct assembly of the heterochromatin and enable it to segregate chromosomes properly.
Earlier studies had hinted that a specific protein component of RITS, called Chp1, might be the key binding molecule that enables RITS to attach to its methylated histone target on heterochromatin. In test tube studies, the scientists found that the Chp1 protein does, indeed, attach very tightly to that modified histone.
To address why Chp1 binds its target so tightly, the Partridge lab collaborated with a team of structural biologists who provided a snapshot view of the molecular details of how Chp1 binds its target. The scientists then compared this information with that for a protein that only weakly binds the same mark. Based on this comparison, they made changes in Chp1 that they predicted would weaken its binding activity. In studies with yeast cells, they found that mutations that only slightly weaken Chp1’s binding activity cripple the generation of heterochromatin and chromosome segregation.
A steady stream of such basic discoveries will ultimately yield a full picture of chromosome segregation and provide critical insights into how it goes awry in miscarriage and cancer.
“We don’t fully understand the cause-and-effect of how chromosome mis-segregation can contribute to tumor formation because we don’t know enough about the basic mechanics of how chromosomes segregate normally,” said Partridge, the study’s senior author. “But if we can learn how it should work in simple organisms like yeast, and then extrapolate those findings to mammalian cells, it could give us a handle on where to look for the genes that might be mutated in these abnormal cells to drive tumor formation.”
Other authors of this paper are Godwin Job and Sreenath Shanker, both of Biochemistry; and Victoria Noffsinger, formerly of St. Jude.
This research was supported in part by National Institutes of Health grants, the Howard Hughes Medical Institute, Cancer Center support grants and ALSAC.