The language of life is about to expand its vocabulary. An international team of researchers discovered that the body's copying machine for DNA works in the same way for manmade, artificial building blocks of DNA as it does for the natural kind.
If scientists find artificial DNA building blocks work well and are safe to use, the extra building materials could create DNA that codes for new molecules that the body can't make now. The artificial DNA could also form the basis of a partly synthetic organism.
The DNA code in living things is made of four different molecules, called bases, that are nicknamed A, T, C and G. In a double row of DNA, the bases always link up to each other in a specific way, with A's matching with T's and C's matching with G's. In 2008, a team of researchers created a third, artificial pair of DNA molecules made to match with each other, named NaM and 5SICS. In this new study, some of the same researchers used a technique called X-ray crystallography to take pictures of A, T, C, G, NaM and 5SICS while they were getting copied in a test tube.
DNA copying is an important bodily process that happens often, so that cells can pass their genetic information on to new cells that are created all the time, such as skin or blood cells that develop to replace old, worn-out cells.
After NaM and 5SICS were made, several other groups of researchers found that a natural strand of DNA with NaM and 5SICS added to it will still copy itself nearly as well as all-natural DNA. Scientists didn't know why it worked so well. They worried they had somehow "tricked" the body's DNA copying machine, called DNA polymerase, said Floyd Romesberg, a chemist at the Scripps Research Institute in La Jolla, Calif. Romesberg was one of the principal inventors of NaM and 5SICS and was involved in this new study, published online yesterday (June 3) in the journal Nature Chemical Biology.
The natural base pairs A, C, G and T have specific shapes and line up neatly with each other along their edges when they're inside a DNA helix. Scientists believe their shape and neat fit are important for DNA polymerase to work properly. On the other hand, NaM and 5SICS aren't shaped anything like the natural bases. They don't use the same chemical bonds as natural bases do and they don't line up edge-to-edge. [ Move Over, DNA, and Meet the More Durable XNA ]
With their X-ray crystallography images, Romesberg — along with colleagues in nearby San Diego, Calif., and in Germany — found that while NaM and 5SICS aren't lined up edge-to-edge inside a strand of DNA, they shift so they are in the correct formation for copying when DNA polymerase comes along. "The DNA polymerase apparently induces this unnatural base pair to form a structure that's virtually indistinguishable from that of a natural base pair," said Denis Malyshev, another Scripps Institute chemist in the study. He and his colleagues think that the chemical bonds the artificial bases use are flexible, so they can shift positions easily.
They also found that when the artificial bases slide inside the polymerase, like a sheet of paper placed inside a copying machine, the polymerase undergoes the same chemical interactions as it does when it works with natural bases. They also found the polymerase refuses to pair an artificial base with a natural base, which is similar to how polymerases will only match A's to T's and C's to G's.
In the future, artificial DNA building blocks like NaM and 5SICS could expand the well-known "A, C, G, T" vocabulary of DNA, according to a statement from the Scripps Institute. Synthetic bases may work even if they aren't shaped like natural bases, as long as they have flexible chemical bonds, the way NaM and 5SICS do.
Romesberg, Malyshev and their colleagues are now working on tweaking NaM and 5SICS so that natural DNA strands with those synthetic bases added will copy even more efficiently, at a rate that's closer to the rate found in all-natural DNA, they wrote in their paper. Once they accomplish that, they can start building synthetic organisms from the ground up. "If we can get this new base pair to replicate with high efficiency and fidelity in vivo [i.e., in a living organism], we'll have a semi-synthetic organism," Romesberg said.
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