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U.Va. Researchers Discover Vital Steps In The Cell Cycle; Findings Appear In This Week's Cell And Nature

August 4, 2000 -- Researchers at the University of Virginia Health System have made two key discoveries about cell division. These findings, which may present new treatment targets for some cancers, are published in this week's issues of Cell (August 4) and Nature (August 3). "DNA is the mission control of our cells, but how our genetic template knows what to do, how to replicate and divide faithfully to each daughter cell, has been a long-standing mystery. With these and other recent discoveries, we have begun to identify controllers for specific parts of the cell cycle," said C. David Allis, the Byrd Professor of Biochemistry at U.Va., who heads one of the research labs responsible for the Cell and Nature studies. "These findings put us closer to complete understanding of the cell cycle which will ultimately have enormous consequences for therapy and drug design, particularly for cancer."

The cell cycle is an ordered set of events, culminating in cell growth and division into two daughter cells. The nucleus of each cell contains genetic information in the form of chromatin, a highly folded ribbon-like complex of deoxyribonucleic acid (DNA) wrapped around a class of proteins called histones. Histones, and specifically processes that modify histones, are thought to play a large role in the complex processes of gene expression and cell division, a process that underlies tissue growth and development. "Because cancer is a disease in which regulation of the cell cycle goes awry, a better understanding of these processes should lead to new cancer treatments," Allis explained.

The Cell paper describes the discovery of enzymes that play an important role in cell division by altering histones through a reversible modification process called phosphorylation. One of these enzymes, known as aurora, is found in excess in human tumors, leading the researchers to believe that aurora can be considered a treatment target for certain cancers.

Separation of the two replicated DNA strands in the nucleus is an essential step in each cell cycle. One of the important parts of this separation is the opening and then tightening of the chromatin. Recent research has suggested that phosphorylation and dephosphorylation (adding and taking away a phosphate) of one of the histones are important to this process. However, there has been a gap in the understanding of what molecules or enzymes add or take away phosphates from the histone.

Allis' team, along with that of M. Mitchell Smith, professor of microbiology at U.Va., and Rueyling Lin, assistant professor of molecular biology at The University of Texas Southwestern Medical Center at Dallas, used yeast and worm models to show that aurora is responsible for adding a phosphate during cell division. The researchers also found that the enzyme PP1 is responsible for taking away the phosphate. These findings reinforce the emerging theme that modifications to histones, and changes in chromatin in general, are key to the normal management of the cell cycle.

The study published in Nature relays the discovery of what Allis calls an additional layer of regulation or an "on/off switch" for a second process that alters histones. Called histone methylation, it is thought to be another step in the cell division process that may regulate the phosphate addition discussed in the Cell paper. In contrast to phosphorylation, very little is known about the function of methylation of histones in cells. But based on experience with phosphorylation, the U.Va. researchers theorized there must be an enzyme that modifies the histone in order for methylation to occur. The researchers pinpointed the enzyme, called SUV3941, that acts as an "on switch" for methylation, a key finding generated in collaboration with a team lead by Thomas Jenuwein of the Research Institute of Molecular Pathology in Vienna, Austria.

The research also showed that the process of methylation has a role in regulating the process of phosphorylation - in other word, methylation appears to happen before phosphorylation. Allis and his colleagues had previously proposed that a series of modifications to histones act sequentially or in combination to form a "Histone Code" that regulates key events during the cell cycle involving changes in chromatin structure and function. The Nature paper provides strong evidence that a "Histone Code" really exists and helps to explain how different processes are integrated and regulated in cells.

"Together these studies underscore that the normal regulation of certain enzymes are vital to cell division and replication and that inappropriate regulation of their activities is closely associated with the formation of cancer," Allis said. "The implications of this research, while basic, are far reaching for human biology and disease."

Contact: Suzanne Morris

FOR ADDITIONAL INFORMATION: please contact the Office of University Relations at (804) 924-7116. Television reporters should contact the TV News Office at (804) 924-7550.
SOURCE: U.Va. News Services


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