The new viral DNA, a breakthrough for biologists?
Some viruses have a mysterious ‘Z’ genome made from an alternate nucleotide.
Since the Watson Crick model (the first-ever model of DNA), we know that the DNA of each and every organism is made of 4 alphabets (A, T, G, C) that represent 4 different chemical bases. Of these four bases, the base A(adenine) binds with the base T(Thymine) by the help of two hydrogen bonds and the base G (Guanine) binds with C(Cytosine) with three hydrogen bonds. The three hydrogen bonds in the G:C base pair makes it more stable and a little harder to break as compared to the A:T base pair which has only two hydrogen bonds).
In 1970, a research team in the Soviet Union discovered a new DNA called the Z DNA in a bacteriophage (type of viruses that invade bacteria and manipulates the bacteria’s enzymes for their own replication) called S-2L. The genome of the S-2L has the chemical base A(adenine) replaced by the chemical base Z(2 amino adenine). This led to the formation of Z:T base pairs, which are contradictory to the traditional DNA models.
This substitution along with a higher number of G: C base pairs(which has stronger bond and thereby requires higher energy to break) made the DNA harder to be affected by external agents (defence systems of bacteria). This substitution of A base pair is believed to serve an evolutionary advantage, it is trusted to be a part of the host evasion tactics which was developed by the bacteriophage (virus also called as phages) in order to protect itself from the antiviral enzymes produced by the bacteria.
For a long time scientist were unaware of how the bacteriophages (or phages in short) produced the Z base and if it was common. Scientists were trying to find answers to these questions since the early 2000s. In 2015 Marliere and the team found a phage that infects aquatic bacteria that belonged to a family called “Vibrio” harbored a gene called that matched a stretch of S-2L’s genome.
In 2019, Zhao’s team found similar matches again, both the team reported to have found a gene called Pur Z, that codes an enzyme that plays an essential role in the making of Z nucleotide. They also identified other enzymes that complete the production of Z nucleotide encoded in the genome of the bacteria that they infect.
They now understood how the Z nucleotide was produced but was still confused about how the phages were able to delete the traditional A nucleotide and insert the Z nucleotide in its place. Both Marliere and Zhao had a slightly different conclusion on this front.
Marliere and team found an enzyme in the viral genome called polymerase, that helps remove any A nucleotide from the DNA and add the Z nucleotide in its place, but Zhao felt that there was more to it than a mere enzyme. She and her team figured out that the increase in the concentration of dZTP (precursor molecule for Z nucleotide) as compared to the dATP( precursor molecule for A nucleotide) levels was enough to trick the polymerase into making the Z DNA.
How is this discovery of bacteriophage with Z DNA beneficial?
There are still so many questions that needs to be answered about these phages, like if their genome would be compatible with regular human genome, and if they could be manipulated for therapeutic use, but it does open a very exciting window of opportunities
What is phage therapy?
Phage therapy uses viruses to kill bacterial infections, although it sounds new this concept has been known for more than 100 years.Phages are highly host-specific and only infect specific species or even subspecies of bacteria.
- They can kill bacteria without any negative effect on human/ animal cells, subsequently, they can be used alone or in combination with antibiotics to treat bacterial infections. Phages being highly specific gave them an upper hand over antibiotics that kill bacteria indiscriminately, especially in cases of bacteria that have developed antibiotic resistance.
- Phage-based nanocarriers for drug delivery and vaccine adjuvants. Although phages naturally target specific bacteria, researchers learned to modify the phages genetically in order to target specific cells or to target several bacterial species. This can help immensely in drug delivery.
- A mixture of phage variants called phage cocktails could now be used to treat patients. Alongside therapeutic applications, they could also be used as diagnostic markers for specific structures.
These concepts are still in clinical trials, there is a long way to go before these phages could be used regularly for human treatment.
Understanding the working of the Z- DNA and the discovery of more phage genomes with Z-DNA could help them understand how the phages benefit from the Z nucleotide.
The fact that they have the genes in hand could hopefully speed up the scientists to understand the potential application of Z-DNA and maybe their potential benefit in phage therapies.
Benner, whose lab created unnatural bases /expanded the genetic alphabets to include four more synthetic bases hopes that this study would rattle researchers into realizing the power of altering the genetic alphabet.
