Study: Hydrogen Bonds Aren't Key To DNA Pairing After All

September 29, 1997

Hydrogen bonds play at best only a peripheral role in the accurate pairing of DNA bases, researchers have shown, overturning the conventional wisdom long been held by biochemists. The finding represents a milestone in researchers' understanding of the workings of DNA -- the genetic bedrock of all organisms -- and forces scientists back to the drawing board to revisit the fundamental question of what's really behind the amazing fidelity of DNA replication.

Eric Kool, the University of Rochester professor of chemistry who led the study reported in the September 30 issue of the Proceedings of the National Academy of Science, suggests that it's now more likely than ever that the distinctive shapes and sizes of each of the four DNA bases underpin the impressive 99.99-percent accuracy of DNA replication. Like a space in a jigsaw puzzle that can be filled only by the one piece with a matching shape, only one base is capable of squeezing into a DNA strand opposite any given partner.

"The apparently inescapable conclusion is that H-bonds are not absolutely required," agrees Myron Goodman, a biologist and DNA expert from the University of Southern California, in a PNAS analysis accompanying Kool's paper. "These results provide an impetus to consider what role H- bonds actually play in stabilizing DNA and enhancing DNA polymerase fidelity. ... The notion that H-bonds alone keep the two strands of a DNA double helix together, found in many textbooks, seems inadequate."

The conclusion is based upon the finding that growing strands of DNA can accurately incorporate a nucleotide that closely resembles the DNA base thymine but lacks the natural base's ability to form hydrogen bonds.

The findings build upon earlier work by Kool that showed that when thymine is replaced in a DNA template by difluorotoluene, a ring-like molecule that very closely mimics thymine's shape but can't form hydrogen bonds, DNA- copying machinery nearly always inserts thymine's normal partner, adenine, opposite the molecular impostor.

When critics pointed out that adenine is the base most commonly inserted when any template base is damaged or missing, Kool and his partners turned the tables and studied whether a polymerase would insert the mimic itself opposite an adenine template. Not only was the mimic inserted opposite adenine, it was chosen as adenine's partner with nearly the same frequency as thymine itself.

"Scientists already know that fluorocarbons such as difluorotoluene are absolutely terrible at hydrogen-bonding -- in fact, the reason why nothing sticks to Teflon is because it's a fluorocarbon," Kool says. "With this finding, if you accept that difluorotoluene doesn't form hydrogen bonds, then you have to accept that hydrogen bonds aren't necessary for accurate replication of DNA."

Kool, who was joined in the research by postdoctoral researchers Rex Ren and Sean Moran, says the finding could have ramifications far beyond the theoretical: Nucleoside analogs are already used as drugs to thwart the enzymes that copy the genes of tumor cells and viruses.

The work was supported by the National Institutes of Health.

University of Rochester

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