Cancer cells, illustration
Credit: JESPER KLAUSEN / SCIENCE PHOTO LIBRARY/Getty Images

U.S. researchers have unveiled a new way in which cells lose their ability to divide, which can affect the body’s ability to regenerate and also promote tumor growth and inflammation.

The researchers report their findings in Nature Structural and Molecular Biology.

The team found that a common form of oxidative damage exclusively occurring at telomeres—located at the ends of chromosomes— could create senescent ‘zombie’ cells that are no longer able to divide.

Telomeres are critical for the stability of the genome, for cellular function and health and the shortening of these structures when cells repeatedly divide has already been linked with senescence in cells.

This study now provides a new way in which damage to telomeres, without shortening them, can rapidly impair the growth of healthy human fibroblast and epithelial cells within just a few days.

“We found a new mechanism for inducing senescent cells that is completely dependent on telomeres,” explained researcher Patricia Opresko, professor of environmental and occupational health and of pharmacology and chemical biology at the University of Pittsburgh in Pennsylvania.

“These findings also solve the puzzle of why dysfunctional telomeres are not always shorter than functional ones.”

The researchers developed a chemoptogenetic tool that produces the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells.

Specifically, they used a protein that bound exclusively to telomeres and had a high affinity to a photosensitive dye. This dye produced reactive oxygen molecules when activated by far red light, which then went on to form 8oxoG when reacting with DNA.

As the dye only bound to telomeres, DNA lesions were created exclusively at the tips of chromosomes.

A single, five-minute production of telomeric 8oxoG induced multiple hallmarks of cellular senescence within just four days.

Removing the p53 gene, which plays a key role in controlling cell division and cell death, remedied the growth reduction thereby implicating p53 signaling in the 8oxoG-induced premature senescence.

Acute 8oxoG production did not shorten telomeres, but instead appeared to generate fragile sites and mitotic DNA synthesis at their location, indicative of impaired replication.

“Now that we understand this mechanism, we can start to test interventions to prevent senescence,” said lead researcher Ryan Barnes, a postdoctoral fellow at Opresko’s lab. “For example, maybe there are ways to target antioxidants to the telomeres to protect them from oxidative damage.”

He added: “By reducing the accumulation of zombie cells, which contribute to degenerative diseases, we might be able to promote ‘healthspan’—the length of time that a person is healthy.”

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