Blind Mole Rats Use Junk DNA to Combat Cancer

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Retrotransposons are DNA sequences that can move about the genome by copying themselves from their RNA transcripts and reinserting into new locations. Also known as jumping genes, these DNA elements, which may be the remnants of ancient viral infections, are generally thought to provide little or no benefit to the host and can even cause harmful mutations. However, blind mole rats (Spalax spp.) use these pieces of so-called junk DNA to protect itself from cancer, reports a study in Nature Immunology last week (September 23)—a discovery that experts say may have implications for human treatments.

“The paper describes an important new mechanistic insight into the way one can trigger inflammatory signals in cancer cells to either kill them directly or make them vulnerable to cancer-killing therapies,” says cancer biologist Stephen Baylin of Johns Hopkins School of Medicine, who was not involved in the research. “The importance of it is really quite profound.”

Blind mole rats are small, furry, subterranean rodents that can live up to 20 years—roughly 10 times as long as a similarly sized mouse. This unusual longevity is explained in part by the animal’s natural resistance to cancer, mediated by the widespread initiation of cell death among rapidly proliferating precancerous cells. The cell death is triggered by increased production of the inflammatory cytokine interferon beta (IFN-β), but what causes IFN-β to ramp-up was unknown.

“It almost looked as if there was some kind of [cell] counting mechanism . . . cells divide a number of times and then this mechanism is triggered and kills the cells,” says Vera Gorbunova, who studies the biology of aging at the University of Rochester and whose team described concerted cell death in blind mole rats in 2012. But analyses of likely counting mechanisms only led to dead-ends, she explains. Had it not been for another project in her lab on age-related retrotransposon activation, the team may have remained stumped.

To stop retrotransposons from jumping around the genome and causing mutations, they are normally silenced by DNA methylation, an epigenetic modification that suppresses gene activity. But as mammals age, says Gorbunova, this epigenetic mechanism fails, and retrotransposons wake up and cause havoc. Importantly, studies in human and mouse cells had shown that retrotransposon activation not only induces IFN-β production, it can have anti-tumor effects by triggering cell death. These findings suggest retrotransposon activation is “a double-edged sword,” says Gorbunova, and they point to a possible mechanism of concerted cell death in mole rats.

Sure enough, when the team compared blind mole rat cells that were dividing normally with those cultured to replicate faster and thus enter concerted cell death, they found retrotransposon RNAs were highly abundant in the soon-to-die cells, as was IFN-β. The level of DNA methyltransferase, an enzyme that methylates DNA, was also lower in the faster replicating cells than in the control cells. Treating the mole rat cells with antiretroviral drugs, which stop retrotransposons copying themselves, prevented concerted cell death.

The team went on to show that the boost in IFN-β production induced an innate immune signaling pathway that was necessary for concerted cell death, and that if mole rat cells lacked this signaling ability, they could be stimulated to form tumors far more readily than cells with intact signaling when transplanted into live mice.

Lastly, the team showed that in cultured human cancer cells, artificially lowering the level of the human DNA methyltransferase DNMT1 or boosting the level of retrotransposons by transfecting in retrotransposon genes could curtail proliferation. This suggests that even though humans have not evolved the same cancer resistance mechanism as blind mole rats, our related cellular machinery could potentially be tweaked to treat cancers, says Gorbunova.

The work was “beautifully done with very interesting observations,” says cancer researcher Jian Xu of UT Southwestern Medical Center who did not participate in the research. “It’s a little bit counterintuitive because we’ve learnt a lot about why mammals and other species like to keep retrotransposons inactive,” he says, but blind mole rats have “actually leveraged [retrotransposons] for their benefit—to eliminate the premalignant cells and prevent cancer transformation.”

If researchers can figure out how blind mole rats achieve this balance of retrotransposon activation, Xu says, it may be possible to develop a treatment that “maximizes the beneficial effects without generating the deleterious [ones].”

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