Stephanie Gross

David Allis

Secrets of the cell discovered
Findings may shed light on new directions for cancer treatments

By Suzanne Morris

Researchers at the U.Va. Health System have gotten closer to understanding what makes cells grow and divide with two key discoveries about enzymes that alter histones. These findings, which may present new treatment targets for some cancers, are published in early August issues of Cell and Nature.

"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, which includes the work 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, 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.

The finding reinforces 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, a key finding done in collaboration with another team led by Thomas Jenuwein of the Research Institute of Molecular Pathology in Vienna, Austria. Called histone methylation, it is thought to be another step in the cell division process that may regulate the phosphorylation discussed in the Cell paper.

"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."