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 act
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Contact: Franklin Hoke
hoke@wistar.upenn.edu
215-898-3716
The Wistar Institute
14-Jan-2001