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Wistar Institute scientists find key piece in gene regulation puzzle

Philadelphia-- For the first time, scientists working in The Wistar Institute laboratory of Ronen Marmorstein, PhD, in collaboration with Shelley Berger, PhD, have determined the three-dimensional structure of a key enzyme involved in gene activation. In nature, this enzyme, which is called GCN5, functions to attach acetyl groups to histone proteins that are bound to DNA to facilitate gene activation. The Marmorstein group has obtained a structure of the histone acetyltransferase (HAT) domain of GCN5 bound to both its histone target and to its coenzyme-A cofactor. Details of this structure appear in the paper, "Crystal structure of Tetrahymena GCN5 with bound coenzyme-A and histone H3 peptide," in the September 2, 1999 issue of Nature.

Earlier this year, this same group of Wistar scientists solved the three-dimensional structure of two other HAT enzymes. The first structure, of PCAF, the human homologue of GCN5, bound to coenzyme-A, appeared in the July 1, 1999 issue of The EMBO Journal. The second structure, of yeast GCN5 in its unbound form, appeared along with editorial commentary in the August 3, 1999 issue of Proceedings of the National Academy of Sciences.

By comparing the structures of the unbound HAT, HAT bound to coenzyme-A and HAT bound to both coenzyme-A and histone, the Wistar group has gained valuable information about the mechanism of histone acetylation. In particular, they have identified the details of how the enzyme carries out its function, the structural adjustments the enzyme needs to make at each stage of its activities, and, most importantly, how it finds its histone target for proper regulation of gene activation.

Histones are proteins that bind to and restrict the activity of DNA in the chromosomes. Before the gene activation can occur, general transcription factor and coactivator proteins must bind to DNA and DNA and histones must be separated through a process that is facilitated by histone acetylation. Scientists
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Contact: Diana Cutshall
dcutshall@wistar.upenn.edu
215-898-3716
The Wistar Institute
1-Sep-1999


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