Stem Cells 2003;21:620-621
www.StemCells.com
© 2003 AlphaMed Press
FUNDAMENTALS OF CANCER MEDICINE |
The Molecular Perspective: Histone Deacetylase
David S. Goodsell
David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu http://www.scripps.edu/pub/goodsell
Our cells contain about 6 billion base pairs of DNA, which encode about 30,000 different proteins. As you might expect, however, we do not need all of this information at all times. At any given moment, each of the cells in your body is using somewhere between one-third and two-thirds of its DNA, and the rest is stored safely out of reach. DNA storage is the job of the histone proteins. In the nucleus, DNA is wound around histones to form nucleosomes, which further associate to form the condensed structure of chromatin. Nucleosomes are highly dynamic, and the information in chromatin can range from deep archival storage to an active lending library.
The transitions between tightly protected chromatin to freely accessible DNA are controlled, in part, through modification of the histone proteins. Each histone contains a long, flexible tail that extends outward from the nucleosome. These tails are essential, but partially redundant: mutational studies in yeast have shown that cells can get by with only three or four of the eight tails in each nucleosome, but run into problems if all of them are removed. In cells, the tails are modified by adding acetyl groups, phosphates, methyl groups, adenosine diphosphate molecules, or even entire ubiquitin proteins. Together, these modifications form a code that determines the current state of the histone. By interacting with other nucleosomes and by interacting with a diverse collection of chromatin-remodeling proteins, these tails help to control the local structure of the chromatin.
Acetylation is an important element in this histone-modification language. The histone tails contain many lysine amino acids, which interact favorably with the many negative charges on the DNA backbone. These tails are thought to wrap around the outside of the nucleosome, stabilizing the tightly coiled structure, and to extend to neighboring nucleosomes, interacting with the DNA and histone proteins there and stabilizing compacted forms of chromatin. Of course, the histones must then let go of the DNA when it is needed to create proteins. One way to release the DNA is to weaken the interaction of the histone tails with other nucleosomes. To do this, the lysine amino acids are acetylated, removing the positive charge. This results in a loosening of the tightly wound chromatin fiber and allows greater access to the DNA by transcription factors and RNA polymerase.
The state of the chromatin at any given moment is controlled by the opposing actions of two types of enzymes, shown in Figure 1
. Histone acetyltransferases add acetyl groups, neutralizing the histone arms and loosening the nucleosomes. Histone deacetylases, on the other hand, remove acetyl groups and lead to the compaction of the chromatin and the silencing of the DNA held inside (Fig. 2). Often, these enzymes are associated with, or are actually part of, a transcription factor that binds to the DNA. Thus, the effects are often localized to given portions of the DNA, and the transacetylase/deacetylase enzymes modify the reading of only a small set of genes.
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Figure 1. Histone acetyltransferase and deacetylase. At the top is HAT1, a histone acetyltransferase. The groove at the top grips the histone tail and transfers the acetyl group provided by acetyl-coenzyme A. At the bottom is a bacterial analog of a histone deacetylase. It has a deep conical pocket with a zinc ion at the bottom. An acetylated lysine fits into this pocket, and the acetyl group is clipped off. The molecule in red is trichostatin A, an inhibitor that was isolated from a fungus. Anticancer drugs that are currently in development are similar in shape to this inhibitor, filling the active site and blocking the action of the enzyme. Coordinates were taken from entries 1qsr
[PDB]
and 1c3r
[PDB]
at the Protein Data Bank (http://www.pdb.org).
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Figure 2. Histone deacetylase in action. A strand of chromatin is shown, with the DNA (in yellow) wrapped around the histones (in green). Each little bundle of eight histones with two loops of DNA is termed a nucleosome. At the top, the tails of the histones are acetylated at many sites (small green dots), leading to an open, accessible form of chromatin. At the center, histone deacetylase (in red) is removing the acetyl groups. At the bottom, the deacetylated histone tails associate with neighboring nucleosomes to form a compact, inaccessible form of chromatin.
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Somewhat surprisingly, recent research has shown that these enzymes are good targets for cancer chemotherapy. Since these enzymes play such a central role in cellular function, we might expect that histone deacetylases or transacetylases would be too sensitive for use in therapy—that the drugs would attack all cells indiscriminately, leading to severe side effects. However, inhibitors of histone deacetylase appear to affect only a small number of genes, most of which are involved in cell growth. When used as drugs, these compounds lead to overly acetylated DNA, which is overly active in the making of proteins. In tumor cells, this often leads to differentiation of the cell, changing the cell from a form that grows without limit to a differentiated type that does not multiply at all. In other cases, the histone hyperacetylation leads to arrest of the cell cycle, stopping further growth, or induces apoptosis, leading to neatly programmed death of the tumor cell.
FURTHER READING
Luger K, Richmond TJ. The histone tails of the nucleosome. Curr Op Genet Dev 1998;8:140–146.[CrossRef][Medline]
Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 1999;98:285–294.[CrossRef][Medline]
Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature Rev Drug Discov 2002;1:287–299.[CrossRef][Medline]
