Common mode of action likely in gene-activation molecules linked to cancers

November 16, 2000

In a just-completed study, two collaborating groups of scientists at The Wistar Institute have identified the structure of a molecule known to regulate gene expression. The molecule, called Esa1, is essential for cell growth in yeast and is related to a human molecule that has been implicated in certain forms of leukemia.

The scientists also compared this new structure with that of several molecules with related function but dissimilar composition. The comparison revealed unanticipated structural similarities, suggesting the molecules likely share a common mode of action, whatever their chemical dissimilarities. The new findings are reported in the November issue of Molecular Cell, to be published November 17.

The ability to turn genes on and off appropriately is key to normal function in all cells, and mutations in the regulatory molecules studied have been linked to an array of diseases, including cancers. The finding that these molecules, known as histone acetyltransferases, or HATs, share important structural features and perhaps a unified mechanism of action highlights the potential value of any anti-cancer drugs that would target this mechanism.

"These molecules help balance the activation and inactivation of genes in the cell in a way that appears to be crucial to health," says Ronen Marmorstein, Ph.D., senior author on the study and an associate professor at The Wistar Institute. "When they are disrupted, disease states such as cancer can result. So, the development of drugs to modify their activity, perhaps based on structural insights, could have significant medical implications."

The study used X-ray crystallography to obtain the structures of the molecules, a much more demanding analytical technique than, for example, DNA-sequence comparisons. But the use of the more strenuous approach proved pivotal.

"We couldn't have anticipated the structural similarities among these molecules from their genetic sequences," says Shelley L. Berger, Ph.D., a co-author on the study and an associate professor at The Wistar Institute. "We needed the structural comparisons to come to the conclusions we came to."

Scientists have only recently begun to fully appreciate the role played by histone acetyltransferases in promoting gene expression. They work in coordination with a related group of regulatory molecules called histone deacetylases, which inhibit the expression of genes.

Both act on histones, which are small proteins around which DNA coils itself to form structures called nucleosomes. Compact strings of nucleosomes, then, form into chromosomes, of which humans have 23 pairs in the nucleus of every cell. When the DNA is tightly wrapped around the histones, the genes cannot be accessed and their expression is repressed. When the DNA coils around the histones are loosened, the genes become available for expression.

Although scientists have yet to fully illuminate the process, they know that histone acetyltransferases add an acetyl molecule to a tail-like structure on the histones, which has the effect of loosening the DNA coils. Histone deacetylases remove an acetyl molecule from the histone tails, causing the DNA to wrap more tightly around the histones. The molecules compared by the Wistar researchers come from the MYST, Gcn5/PCAF, and Hat1 families of histone acetyltransferases, with Esa1 being a member of the MYST family.
-end-
The lead author on the study is Yuan Yan, B.S. In addition to Marmorstein and Berger, the other co-authors are Nickolai A. Barlev, Ph.D., and Randall H. Haley, B.S. Funding for the work came from the National Institutes of Health.

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.wistar.upenn.edu), to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science, and to the public interest newswire AScribe (http://www.ascribe.org).

The Wistar Institute

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.