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An international research team led by Hiroki Shibuya at RIKEN Center for Biosystems Dynamics Research (BDR) in Japan has solved a genetic mystery and revealed a previously unknown way that DNA can control what cells do.

Published in Science, that in the roundworm C. elegans, vital RNA needed to keep the ends of chromosomes intact does not have its own gene. Instead, it hitchhikes inside another one. DNA hitchhiking could be a common strategy in the animal kingdom, and has implications for anti-aging therapies and regenerative medicine in humans.

Telomeres are DNA caps that protect the ends of chromosomes, much like the plastic tips of shoelaces. As we age, the cells of our bodies—called somatic cells—divide when we need new tissue, and every time that happens the telomeres lose some of their DNA.

Some signs of aging are related to this process. For example, skin cells with shorter telomeres make less collagen and skin becomes wrinkled. When they are too short, cells self-destruct.

Sperm and egg precursor cells—collectively called germ cells—are an exception to this rule. When they divide, an enzyme called telomerase adds replacement DNA to the ends of shortened telomeres. Because of this, telomere length doesn't get shorter with each generation, and species do not become extinct.

Telomerase contains an RNA template that is used to make the replacement DNA. In humans and other mammals, this RNA comes from the TERC gene. C. elegans has working telomerase, but it doesn't seem to have a TERC gene.

This mystery has stumped scientists for more than 20 years, and some have assumed that the gene was lost during evolution. In their study, the team at RIKEN BDR discovered how C. elegans can exist without a standalone TERC gene.

Because telomerase levels are normally very low, the researchers genetically engineered C. elegans to overproduce the telomerase protein, which made it possible to collect large amounts of the whole telomerase complex, including the RNA template.

They then used all the collected template RNA to search the genome for matching DNA. Unlike in mammals, instead of being located in its own gene, they found it inside another gene's intron.

Usually, the instructions in DNA within genes are used to build proteins. But some parts of genes, called introns, are not used to build proteins and are usually removed and discarded once the gene's protein is made.

"It was surprising to find that the key RNA—which we have named terc-1—was hidden inside an intron of the gene called nmy-2, which is expressed only in germ cells," says Shibuya. "Indeed, the discovery that the essential telomerase RNA was hidden within an intron was completely unexpected."

Experiments showed that in C. elegans lacking terc-1, telomeres became shorter each generation, and within 15 generations, the animals became extinct. Inserting terc-1 inside introns of other genes that are expressed in germ cells created roundworms that had normal telomeres and did not become extinct.

In contrast, when terc-1 was inserted into introns of genes that only activate in somatic cells, the animals did become extinct. Thus, by hitching a ride inside genes activated in germ cells, terc-1 is produced where it is needed—the germ cells. There, it helps ensure that future generations do not receive shortened telomeres, thus supporting the survival of the species.

Is this a unique instance of a functional RNA located in an intron and regulated by the host gene? The researchers do not think so.

"Although we discovered this intron hitchhiking strategy in C. elegans, similar mechanisms are likely used by other non-coding RNAs or exist across different species," says Shibuya.

"This method of embedding RNAs so that the timing and location of their expression are automatically controlled by the host gene points to a broader principle in biology."

"Beyond its evolutionary significance, this discovery will help us better understand how telomerase is regulated in healthy cells and could transform approaches to aging, fertility, and regenerative medicine."