Molecular Imposter Rebuts Long

February 26, 1997

Ever since Watson and Crick first cracked the structure of DNA in 1953, biochemists have speculated that hydrogen bonding between DNA's four bases plays a key role in the amazing accuracy of this genetic blueprint. But new research with a molecular imposter is calling some of these long-held beliefs into question. Results presented in the February 12 issue of the Journal of the American Chemical Society suggest strongly that the precision of DNA copying has much more to do with DNA's shape and the enzymes that copy it.

This finding brings into question decades of dogma on DNA replication, says researcher Eric Kool of the University of Rochester. Kool adds that the new information may help researchers develop new drugs that are better able to sneak in and kill sickly cells -- including deadly cancer cells.

Kool and co-workers created a ring-like molecule that very closely mimics the shape of the base thymine in DNA. This thymine mimic lacks the slightly charged regions needed to form hydrogen bonds with thymine's normal partner base, adenine. But when the mimic was placed into a strand of DNA, the scientists got a surprise: The cell's DNA-copying machinery correctly inserted adenine opposite the thymine-like base despite the absence of hydrogen bonds. Not only was adenine inserted opposite the thymine mimic, it was inserted correctly nearly all the time -- suggesting that base shape is more important than hydrogen bonds in ensuring accurate DNA replication.

"Most biochemistry textbooks cite hydrogen bonds as the primary reason that DNA is copied accurately," says Kool, a professor of chemistry. "Because of this finding, the next generation of texts may not be able to say that."

Hydrogen bonds form because of slight charge differences between the atoms that make up adjacent molecules. Each of the four DNA bases -- adenine, thymine, cytosine, and guanine -- has a characteristic arrangement of these partially charged atoms that exactly complements its partner base. It's the resulting matching of atoms with slight positive and negative charges that biochemists have thought critical to the 99.99 percent accurate pairing of bases in DNA.

"It now appears that the shape of the DNA bases may be the chief mechanism by which DNA-replicating enzymes select the right bases to insert into a growing strand," Kool says. "The enzyme might form a tight pocket around the DNA template which allows only correctly shaped bases to be added" -- like an empty space in a jigsaw puzzle that can only be filled by the one puzzle piece that has a matching shape.

Kool believes researchers haven't seen these results before because they've used synthetic DNA bases with shapes significantly different than the bases they were trying to mimic. When correct DNA synthesis failed to occur with these misshapen bases, researchers blamed the lack of hydrogen bonds rather than the distorted base shapes.

The Rochester research team will next try to assess the behavior of the thymine mimic in transcription, the process that converts DNA into RNA in preparation for protein production. Kool says that if the mimic base blocks transcription, it will have strong potential as a drug -- infiltrating cancerous or diseased cells like a Trojan horse and then knocking them out by blocking genetic expression. Kool also plans to examine shape mimics for the other three DNA bases.

Kool was joined in the research by postdoctoral researchers Sean Moran and Rex Ren and graduate student Squire Rumney IV. The research was funded by the National Institutes of Health.
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University of Rochester

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