Philadelphia - In the world of human genetics, a key challenge for researchers is to understand how genes are switched on and off. In a sense, the regulatory molecules that determine which of the estimated 60,000 genes in any human cell are active or inactive at a given time do as much as the genes themselves to define the character of that cell, whether it be a skin, eye, liver, or other type of cell. Certainly, precise gene regulation is critical for health, and flaws in these molecules have been linked to many serious medical conditions.
Now, two collaborating teams of scientists have identified the three-dimensional atomic structure of the switching subunit of one of the most common of these regulatory molecules. First observed in a gene-regulating molecule in plants, this critical subunit, called a domain, has since been found repeated more than 400 times throughout the plant and animal kingdoms. Mutations in the domain - referred to as the plant homeodomain, or PHD - have been implicated in a variety of human diseases, including childhood leukemias and other cancers, certain forms of autoimmune dysfunction, and a mental-retardation syndrome, ATRX. In the parlance of gene regulation, the PHD domain is a repressor, meaning that it turns genes off.
A report on the new study from two laboratories at The Wistar Institute and the Mount Sinai School of Medicine appears in the January 15 issue of the EMBO Journal.
"Having in hand the molecular structure for this widely occurring gene switch begins to help us explain why mutations in this molecule can lead to cancers and many other diseases," says Wistar professor Frank J. Rauscher III, Ph.D., a co-corresponding author on the study and deputy director of the Cancer Center at Wistar. "Our hope, too, is that we may now be able to design drugs to inhibit the molecule when there are problems with it or, ideally, even to rescue it to restore its proper function."
"PHD domains can be thought of as the active or business ends of these gene-regulating molecules," explains Katherine L.B. Borden, Ph.D., co-corresponding author, with Rauscher, on the study and an assistant professor of physiology and biophysics at the Mount Sinai School of Medicine. "One region of the molecule latches on to the gene much like planting one's feet on the ground, whereas using one's arms - the active region - does the work of turning a gene on or off."
The two collaborating laboratories were responsible for distinct aspects of the study. Rauscher and his colleagues at Wistar identified the PHD domain and its importance, and produced and purified quantities of the PHD protein using recombinant DNA technology. Borden and her coworkers at Mount Sinai then used nuclear magnetic resonance, or NMR, to analyze the structure of the molecule. The use of NMR allowed the structure of the PHD molecular subunit to be determined without disturbing its natural shape and orientation.
The Rauscher and Borden laboratories collaborated equally to produce this discovery. The lead author is Allan D. Capili at the Mount Sinai School of Medicine, and David C. Schultz at The Wistar Institute is a co-author. Support for the work was provided by National Institutes of Health and the American Cancer Society. Borden is also a Leukemia and Lymphoma Society Scholar.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the basic mechanisms underlying major diseases, including cancer and AIDS, and to developing fundamentally new strategies to prevent or treat them. The Institute is a National Cancer Institute-designated Cancer Center - one of the nation's first, funded continuously since 1968, and one of only ten focused on basic research. Founded in 1892, Wistar was the first institution of its kind devoted to medical research and training in the nation. News releases from The Wistar Institute are available to reporters by direct e-mail or fax upon request. They are also posted electronically to Wistar's home page (http://www.