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Dozens of viruses seem to use a different DNA base

Image of two chemical structures.
Enlarge / Normal DNA uses adenine (left), while some viruses use diaminopurine instead.

DNA is the genetic material used by every living organism. But, in a few edge cases, the four bases of DNA—adenine, thymidine, cytosine, and guanine—undergo chemical modifications. And in viruses, things are far more flexible, with many using RNA instead of DNA as their genetic material. In all these cases, the base pairing in the genetic material takes place according to the rules that James Watson and Francis Crick first proposed.

Until now, there was a single exception, a virus that infects bacteria and uses its own, seemingly unique base. But researchers have finally looked in more detail, and they’ve discovered that this “Z-DNA” seems to be used by dozens of viruses.

Not that Z

Confusingly, there’s something else called Z-DNA. The DNA in our cells has a right-handed curve, called B-DNA, to its double helix. But it’s also possible to have a double helix with a left-handed curve, called Z-DNA.

But that DNA isn’t this DNA. This DNA is distinguished by a base, found nowhere else, that undergoes a different type of base pairing. Diaminopurine, awkwardly abbreviated as Z, is structurally similar to the adenine (A) found in normal DNA. But diaminopurine has an extra nitrogen hanging off one side that lets it form an additional hydrogen bond with A’s normal partner, thymidine (T). A Z-T base pair would thus hold DNA’s double helix together a bit more than a standard A-T pairing.

DNA incorporating Diaminopurine is called Z-DNA. We’ve known since 1979 that it exists in nature in the form of a single virus called S-2L, which infects cyanobacteria. But until now, we didn’t know if that virus was a one-off oddity or represented the tip of a biological iceberg, with lots of viruses we haven’t discovered yet using it. Just as critically, we weren’t even sure of how it ended up incorporated in the virus in the first place.

A large team of researchers, largely from China, decided to figure out what’s going on here. They started by searching the S-2L virus’s genome to figure out whether it encoded anything unusual.

Making a Z

One of the genes present in the S-2L virus’s genome encodes a protein that is related to the one that cells use to make adenine, the base most similar to Z/diaminopurine. A careful look at the protein it encodes, however, reveals that several of the amino acids that are involved in catalyzing chemical reactions are different. These changes affect what molecules can fit into the catalytic site on the protein encoded by the gene. A search of additional viral genomes showed that one of these specific changes is found in dozens of other viruses.

The researchers made some of the viral protein and incubated it with the raw materials used by the normal version of the enzyme. They found that instead of making a precursor of adenine, the protein made a precursor of Z/diaminopurine. Another enzyme found in bacteria then converted it into the mature Z-DNA base. So the virus carries everything it needs to make its own Z-DNA.

Looking at the dozens of viruses that have a similar version of this gene, the researchers found that it was present in genomes that contained a couple of additional genes. One of these genes seems to be involved in ensuring that there’s enough chemical precursors around that can be converted into Z/diaminopurine. The other simply removes all the phosphates hooked up to adenine bases. These phosphates are essential to the use of adenine bases in forming DNA, so the gene essentially depletes the pool of useful adenine and, thus, the cell’s ability to make any DNA but Z-DNA.

In addition, all these genes were typically found together with a specialized DNA polymerase, the enzyme that makes new copies of DNA. This enzyme is adapted to use Z/diaminopurine when copying DNA, although it can still incorporate the normal base as well.

In any case, the researchers found over 60 viral genomes that contain some combination of these four genes. Z-DNA is apparently a regular feature of viral life.

But why?

The obvious question is why life would go to all this trouble to have its own chemically distinct form of DNA. The answer is in how bacteria protect themselves from viruses. One of their main forms of defense are enzymes that recognize specific sequences in DNA and cut them. These bacteria chemically modify their DNA in a way that keeps it from getting cut, meaning the enzymes will only cut foreign DNA, like that of viruses.

Z-DNA, it turns out, can’t be recognized by these cutting enzymes. So the virus completely avoids this kind of defense. The researchers tested a variety of cutting enzymes and found that any that would normally have an A at the targeted spot failed to cut. This indicates that the Z/diaminopurine bases interfere with the enzymes’ ability to recognize any DNA that contains it. For the virus the researchers tested here, there were no signs of any adenosine bases—everything was Z-DNA.

Aside from showing that Z-DNA is far more extensive than a single virus, there are a lot of intriguing implications. Perhaps the most significant is that diaminopurine has been identified in a meteorite, suggesting that it can form spontaneously without too much trouble. That finding is consistent with the idea that some of the chemicals that sparked life might have arrived on Earth from space. It would, however, raise the question of why diaminopurine ended up replaced by adenine at some later point.

There are also a lot of potential uses for alternative forms of DNA. The Z-T base pairs, as we mentioned above, should form more stable interactions than A-T pairs; this could be useful in cases where researchers are using DNA for structural or computational purposes. And a form of DNA that isn’t readily recognized by the proteins in most cells has a lot of potential uses.

Finally, it’s just an intriguing indication that despite so many years of study, life still has some surprises for us.

Science, 2021. DOI: 10.1126/science.abe4882  (About DOIs).

Listing image by Getty/Tek Image/Science Photo Library


Correction: got the right helical form and details on the polymerase’s base preference.

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