DNA Alphabet Can Be Expanded

Scientists at the Scripps Research Institute have found that unnatural DNA bases can replicate just as efficiently as the four main bases. The findings show the genetic alphabet can be expanded and could lead to more precise molecular probes and even new, useful life forms.

DNA is naturally composed of four main bases: adenine (A), thymine (T), cytosine (C), and guanine (G). Adenine pairs with thymine, and cytosine pairs with guanine. Researchers, however, were able to create the bases NaM and 5SICS which DNA polymerase, the structure reponsible for replicating DNA, recognized and replicated efficiently.

"We now know that the efficient replication of our unnatural base pair isn't a fluke, and also that the replication process is more flexible than had been assumed," said Floyd E. Romesberg, associate professor at Scripps Research, principal developer of the new DNA bases, and a senior author of the new study.

The bases NaM and 5SICS do not follow the Watson-Crick geometrical model to form a normal DNA double-helix. Instead, they are looser and join in a way that a DNA polymerase normally wouldn't recognize as a replicatable pair. Somehow, the two bases still replicated efficiently in repeated tests.

"We wondered whether we were somehow tricking the DNA polymerase into recognizing it," said Romesberg. "I didn't want to pursue the development of applications until we had a clearer picture of what was going on during replication."

NaM and 5SICS do not form hydrogen bonds, and integrate themselves into a double-helix using hydrophobic forces. This means that the structures are afraid of water, and will cling together. One example of hydrophobic bonds can be demonstrated by oil, which will cling together in a watery medium.

"It's very possible that these hydrophobic forces have characteristics that enable the flexibility and thus the replicability of the NaM-5SICS base pair," said Romesberg. "Certainly if their aberrant structure in the double helix were held together by more rigid covalent bonds, they wouldn't have been able to pop into the correct structure during DNA replication."