Scientists Uncover an Ancient Link Between Viral Defense and Chromosome Protection

A new antiviral defense system discovered by Columbia scientists could be adapted in the future into a gene editor that slows down aging in our cells and improves cancer therapies.

At the same time, the discovery also shines a light on an ancient event in evolution that may have helped set the stage for the emergence of higher organisms.

The newly discovered system, called DRT10 (for Defense-Associated Reverse Transcriptase 10), protects bacteria from viruses, like the CRISPR antiviral system discovered decades ago that has since unleashed a new era of genome engineering.

But unlike CRISPR, which works by cutting DNA, DRT10 employs a reverse transcriptase, an enzyme that gives it the power to manufacture DNA within the cell.

“It's a very exotic system that departs from the typical way we think about genome engineering,” says Samuel Sternberg, professor of biochemistry and molecular biophysics at Columbia University Vagelos College of Physicians and Surgeons, investigator with the Howard Hughes Medical Institute, and the study's senior author.

“Instead of cutting DNA like CRISPR, or swapping one letter of genetic code like base editors, this system uses RNA as a template to write new sequences of DNA. That gives us a different starting point for building tools to engineer cells.”

The story of DRT10’s discovery, and a first look at its mechanisms, were published today in a paper in Nature. The study also reveals a likely and surprising relationship between the bacterial defense system and telomerase, an enzyme needed by nearly all higher organisms to replenish telomeres—the protective stretches of DNA at the ends of our chromosomes.

“This is a powerful example of how basic research can illuminate deep questions about aging, cancer, and the evolution of life,” says Sternberg. “Studying how bacteria defend themselves against viruses has revealed an unexpected connection to one of the most consequential enzymes in human biology.”

DRT10 discovery

The Sternberg lab is known for searching the genomes of bacteria and archaea for the inventive methods these age-old organisms possess to control and sometimes alter their genomes.

One group of bacterial DNA-writing enzymes—aptly named the “Unknown Group” in 2008—grabbed the lab’s attention for its dozens of reverse transcriptases with still unknown functions. Because reverse transcription creates new DNA from strands of RNA, the enzymes are considered promising starting points for creating new gene editing tools to write new therapeutic sequences into the genome.

“We had this large family of enzymes that could write DNA, but almost no idea what bacteria were using them for,” says Sternberg. “That was an irresistible biological mystery with the potential to yield entirely new biotechnology tools.”

Stephen Tang, a graduate student in the lab, found DRT10 in that group and discovered that DRT10 uses its reverse transcriptase to fight viruses by creating a long piece of DNA with a repetitive sequence read from a template RNA. Tang worked alongside fellow co-first authors Josephine L. Ramirez and Qixiang He and an international team, with Ramirez leading the biochemical studies and He and Israel S. Fernández leading the structural work that revealed how DRT10’s protein and RNA components fit together.

As Tang dug deeper to understand how the reverse transcriptase operates, he realized that the enzyme works a lot like telomerase—a reverse transcriptase found in an evolutionarily distant group of organisms: us.

Potential clinical applications

The similarity between telomerase and the bacterial antiviral system immediately suggested some clinical applications for DRT10.

In humans (and most organisms in the eukaryotic domain of life, including yeast, plants, fungi, and animals), telomerase creates DNA caps to protect the ends of our linear chromosomes.

Sternberg and his laboratory hope to explore whether DRT10 could eventually be adapted to address diseases caused by defects in telomere maintenance, known as telomeropathies.

“It’s early days, but we’re excited by the possibility of turning a bacterial defense enzyme into a tool to rebuild protective DNA at chromosome ends,” says Sternberg.

Telomere shortening causes aging cells to senesce, and the accumulation of senescent cells is linked to several age-related diseases, raising the possibility that restoring telomeres could help preserve healthy cell function.

The lab has already used DRT10 to synthesize human telomeric DNA repeats in human cells and is now working to determine if chromosome lengthening can prevent cells from senescing and extend their healthy lifespans.

One potential application is CAR-T cell therapy, which engineers a patient’s T cells to recognize and attack cancer cells.

“We’re interested in whether maintaining and lengthening telomeres could help therapeutic T cells remain active for longer,” says Sternberg. “DRT10 gives us a brand-new way to explore that question.”

Evidence for a shared evolutionary origin

The similarity of DRT10 to telomerase might have remained an interesting footnote, except for a visit to the Sternberg lab from Mario Rodríguez Mestre, a colleague at the University of Copenhagen who uses computational methods to identify and classify bacterial defense systems.

During a talk, Mestre showed a preliminary evolutionary tree of all reverse transcriptases, color-coded by domain of life. One side of the tree was almost all brown with the bacterial enzymes, the other side turquoise with eukaryotic enzymes.

“I interrupted Mario, really intrigued by a turquoise sliver of eukaryotic reverse transcriptases that clustered very tightly with the bacterial RTs,” says Sternberg. That turquoise streak turned out to be telomerase. “It was a kind of eureka moment, that the functional similarities between DRT10 and telomerase might reflect a common evolutionary origin rather than coincidence or convergence. That allowed us to unify what seemed like two different fields into a single large family of enzymes.”

Additional evolutionary analyses support a common origin for bacterial DRTs and telomerase, suggesting that their ability to synthesize repetitive DNA arose in a common ancestor, before being adapted to maintain linear chromosomes in eukaryotes.

“It’s possible that ancient enzymatic capabilities of a DRT10-like system were part of the molecular machinery necessary for the eukaryotic branch of life to emerge using a different, linear chromosomal topology,” Sternberg says.

“I hope the discovery of DRT10 will lead to valuable clinical advances, but for me, it’s also an awe-inspiring look back at how life evolved.”