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© 2003 AlphaMed Press
The Molecular Perspective: Histone Deacetylase
Correspondence: 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 Website: http://www.scripps.edu/pub/goodsell
Identify the structure and function of histone deacetylase and its role in cancer treatment.
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LEARNING OBJECTIVES
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Learning Objectives
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After completing this course, the reader will be able to:
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 a 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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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.
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FURTHER READING |
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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]
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