Stem Cells, Vol. 18, No. 2, 148-149,
March 2000
© 2000 AlphaMed Press
Fundamentals of Cancer Medicine |
The Molecular Perspective: DNA
David S. Goodsell
David S. Goodsell, Ph.D., 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 WorldWideWeb:http://www.scripps.edu/pub/goodsell
DNA is our most familiar molecule. Barely a day goes by without some mention of it. Suddenly, with bioengineered vegetables and genetic fingerprinting, DNA is newsworthy. Mention DNA and a host of images comes to mind: the trial of O.J. Simpson; picketing consumers in the United Kingdom; ampoules of insulin and growth hormone; and more futuristic visions of world-spanning plagues or perfectly tailored children. The familiar DNA double helix runs through all of this, a pervasive icon of the new era of biotechnology.
But take a moment to think of DNA as a target. At the center of every cancer cell are strands of DNA that match normal DNA except for a few transforming lesions. These changes might provide a handle allowing us to attack cancer at its root. If we can recognize these mutated DNA sequences and target them selectively, we might spare normal cells throughout the rest of the body. To specifically target a single site, we need to recognize a segment about 16 base pairs long. Shorter sequences are typically found in several places in the 6 billion nucleotides of the human genome, and a shorter targeting agent will bind indiscriminately to these sites as well as the preferred, mutated site.
The DNA double helix is designed to be read. It simply bristles with information. Sheltered safely inside is the genetic information, encoded in the matching of adenine with thymine and cytosine with guanine. To use this information, the helix must be unwound, exposing the hydrogen bonding groups normally locked inside. But this is far from the end of the story: abundant epigenetic information is also available for specific recognition.
The double helix leaves two edges on each base exposed; one edge in the minor groove and the other in the major groove. This information is every bit as useful as the Watson-Crick base pairing used for genetic information, and is widely used by DNA-binding proteins and by medicinal chemists.
Anti-cancer drugs that attack DNA use this epigenetic information to target their preferred DNA sequences. They all fall short of the ideal of targeting a single site in the genome, however. In fact, drugs that recognize more than two or three base pairs are rare. Examples include cisplatin and mustards such as cyclophosphamide, which crosslinks adjacent purine bases, and intercalating drugs such as dactinomycin and the anthracyclines, which recognize one or two bases at best. Nonetheless, these drugs are effective in spite of their weak specificity and are widely used in chemotherapy.
An experimental class of anticancer agents is under study now, with the goal of creating a tailored treatment for each individual. These are crescent-shaped molecules that fit within the narrow minor groove of DNA, tightly contacting the edges of the bases found there and forming specific interactions. These molecules are modular, built of pieces that interact with a single base. The natural molecule netropsin, used by a species of Streptomyces for biological warfare, provided the first module, which binds tightly to adenine, cytosine, and thymine, but not to guanine. Modules specific for guanine and for thymine have subsequently been designed. True sequence-specific DNA-binding molecules—termed "lexitropsins"—can now be synthesized and are currently being optimized and tested for use as "designer" anticancer drugs.
Additional Reading:
- Dervan PB. Design of sequence-specific DNA-binding molecules. Science 1983;232:464-471.
- Dickerson RE. The DNA helix and how it is read. Sci Am 1983;249:94-111.
- Walker WL, Kopka ML, Goodsell DS. Progress in the design of DNA sequence-specific lexitropsins. Biopolymers 1997;44:323-334.
- Gottesfeld JM, Neely L, Trauger JW et al. Regulation of gene expression by small molecules. Nature 1997;387:202-205.
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Figure 1. Reading epigenetic information. Each DNA base has three edges that are used for transfer of information. In the DNA double helix, the edge used for encoding the genetic information is buried between strands, in the base pairs discovered by Watson and Crick. The remaining two edges are exposed in the double helix, in the major groove, shown at top here, and in the minor groove, shown at the bottom. The arrangement of chemical groups is unique for each base pair, allowing base pairs to be specifically targeted. In the figure, hydrogen bond-accepting groups are labeled "A" and donors are labeled "D", the large methyl group on thymine is marked with an asterisk, and small carbon-bound hydrogen atoms are marked with a dash. Notice the different patterns in each groove, allowing each of the bases to be distinguished.
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Figure 2. DNA recognition. Epigenetic information is used for specific targeting both by medicinal chemists and by Nature. A small lexitropsin (a sequence-reading molecule) is shown on the left in green, bound in the minor groove of the DNA. It is composed of two small chains, each of which binds to one of the DNA strands, feeling for the differences between the four different bases. A transcription initiation complex, shown in green on the right, takes a more aggressive approach, grabbing the DNA and bending it as it binds. Note that this picture is idealized, omitting nucleosomes and the many other proteins present in actual nuclei. The coordinates were taken from the Protein Data Bank, with accession codes 334d and 1ais.
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