October 21, 2005 — Researchers discovered a special type of molecular structure that helps keep genes properly turned off until the structure is ejected from those genes in a regulated manner to help turn the genes on.
The discovery is reported in the Oct. 21 issue of the journal Cell by scientists from the Huntsman Cancer Institute at the University of Utah.
In all organisms, the genome is split into chromosomes (compressed long strands of DNA) which are subdivided into functional DNA segments called genes. Genes function as the blueprints for building particular pieces of cellular machinery. However, different types of cells each require different types of cellular machinery, and must produce that machinery according to a biological timetable. A central issue in molecular biology is finding out how a cell regulates which genes are on, or active, and which genes are off, or repressed. This topic has direct relevance to human disease, as improper activation or repression of genes that regulate cellular growth is a common feature of cancer cells.
“We must understand how genes are activated or repressed in normal cells in order to understand how this process is misregulated in cancer cells,” says Brad Cairns, Ph.D., lead scientist on the study and an investigator with Huntsman Cancer Institute. “We are beginning to understand how gene activation and repression is altered in cancer cells, and how that leads to tumor growth. However, the design of targeted treatments that can correct these alterations will require a deep knowledge of the basic cellular mechanisms that regulate gene expression.”
The scientists studied a group of proteins known as histones, which form disk-like structures called nucleosomes when they are wrapped by genes. Under an electron microscope, the nucleosomes look like beads strung along the DNA strand. Normal nucleosomes block access to the cellular machinery that reads the blueprint stored in the gene, keeping the gene off or repressed.
Huntsman Cancer Institute investigators discovered that certain genes contain a special type of nucleosome bearing a protein called Htz1. This Htz1-containing nucleosome was shown to be “fragile,” meaning it is ejected from the gene in a regulated manner, allowing reading of the gene’s instructions by the cellular machinery. When the gene returns to its inactive or repressed state, the Htz1 nucleosome is reconstructed, again blocking the machinery from reading the gene.
Cairns, an associate professor in the Department of Oncological Sciences at the University of Utah School of Medicine and an investigator with the Howard Hughes Medical Institute, along with Huntsman Cancer Institute graduate students Haiying Zhang and Douglas N. Roberts, studied yeast cells to make the discovery.
“We and hundreds of other laboratories world-wide use yeast as a model system to study gene expression, as the analytical tools for studying yeast are actually more advanced than those available for human cells. However, all the factors that we study in yeast have virtually identical counterparts in human cells, so we fully expect the discovery to apply in humans as well,” Cairns says.
Huntsman Cancer Institute’s mission is to understand cancer from its beginnings, to use that knowledge in the creation and improvement of cancer treatments, to relieve the suffering of cancer patients, and to provide education about cancer risk, prevention, and care.
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