But the biggest surprise was that the viruses had a polymerase enzyme dedicated to pairing Z bases with Ts during DNA replication. “It was like a fairy tale,” said Marlière, who hoped to find such a polymerase. “Our wildest dreams have come true. “
Indeed, although scientists have discovered other examples of bacteriophages making nucleotide substitutions, it is “the first polymerase to actually selectively exclude a canonical nucleotide,” said Peter Weigele, a researcher at New England Biolabs who studies the biosynthesis of non-canonical bases. The system has evolved to allow “reprogramming,” said Romesberg, reprogramming that could potentially provide new information about how polymerases work and how to design them.
Z and other modified DNA bases appear to have evolved to help viruses escape the defenses with which bacteria break down foreign genetic material. The eternal arms race between bacteriophages and their host cells probably provides enough selection pressure to affect something seemingly “sacrosanct” like DNA, according to Romesberg. “Right now everyone thinks the changes only protect DNA,” he said. “People almost trivialize it. “
But something more may be at work: the triple bond of Z, for example, could add to the stability and rigidity of DNA, and possibly influence some of its other physical properties. These changes could provide benefits beyond hiding bacterial defenses and could make these changes more important.
After all, no one really knows how many viruses may have played with their DNA like this. “Standard [genome sequencing] methods of searching for biological diversity in nature would not find them, ”said Steven benner, a Foundation for Applied Molecular Evolution chemist in Florida who synthesized several artificial base pairs, “because we’re looking in a way that assumes a common biochemistry that isn’t present.”
These types of overlooked substitutions might even show up in more than just viruses. “Maybe we missed some of that in the bacterial world, right?” ” noted Chuan He, chemical biologist at the University of Chicago.
Synthetic biology has (again) shown that it is possible. For years, the Marlière team has been evolving E. coli which use a modified base instead of T nucleotides. Huimin Zhao, a chemist at the University of Illinois at Urbana-Champaign and leader of some of the recent work on the Z genome, is trying to get E. coli and potentially other cells to incorporate Z like viruses do.
Romesberg believes these findings could raise questions about changes in bacterial DNA that were believed to be epigenetic – that is, changes to nucleotides after DNA synthesis, usually to influence expression. of genes. The Z substitution, he said, “shows that things that you might have thought were epigenetic might not be.”
“I think people have to look under rocks that we thought were understood,” he added. “That’s where the surprises come from.
But there is also a lot of room for surprises in less well-studied places, because “we cannot grow most of the microbes on Earth,” said Carol Cleland, philosopher of science at the University of Colorado, Boulder. “Are there other things that we just can’t recognize? “
Marlière wonders, for example, if scientists could one day come across more than one type of basic modification in the same genome. Or maybe they’ll find a change in the molecular skeleton of DNA, in which case “it wouldn’t be DNA anymore,” he said. “It would be something else. “
We need to “stop taking the components of molecular biology as we know them for granted,” Freeland said. “Purely because our instrumentation has improved and we have taken a closer look, everything that we thought was standard and universal is disappearing. “
Original story reprinted with permission from Quanta Magazine, an independent editorial publication of Simons Foundation whose mission is to improve public understanding of science by covering developments and research trends in mathematics and the physical and life sciences.
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