A molecular path toward DNA health

Marta Markiewicz-Potoczny studies molecular pathways: the stepping stones our cells use to send signals (like hunger) and substances (like hormones) throughout the body.

Markiewicz-Potoczny, an assistant professor of biochemistry and molecular genetics in the College of Medicine, identified a molecular pathway that's critical for keeping DNA healthy. The discovery has implications for healthy aging and preventing diseases like cancer.

"We knew this pathway existed, but its unexpected link to DNA health is brand new. It just shows how much we still have to learn about the human body. We're discovering new ways that cells use to keep themselves healthy all the time," Markiewicz-Potoczny said.

Telomeres are chromosomes' end caps

Wrap DNA around proteins and you have chromosomes: the x-shaped structures in the center of our cells. The chromosomes in our bodies are long and thin, like shoelaces, and telomeres sit on the ends like the aglets on the ends of shoelaces.

Telomeres are made of repetitive DNA sequences. They stop DNA from fraying, tangling or mistakenly linking up with other chromosomes. As cells divide, their telomeres shrink - a "hallmark of aging," Markiewicz-Potoczny said. "The older we become, the shorter (our telomeres) get."

Abnormally long telomeres can signal trouble as well. Cancer cells, for example, divide uninhibited while maintaining long telomeres.

What makes telomeres tick?

Telomeres require a "glue" that keeps them from unraveling. It's made of binding proteins called shelterin. One of these proteins is called TRF2.

Scientists have observed TRF2 protecting telomeres in human and mouse cells. Strangely, stem cells from mouse embryos manage to fare well even without the shelterin protein.

"Something is stepping in to protect the telomeres in the absence of TRF2," Markiewicz-Potoczny said. "But what is it?"

A no-nonsense solution

To identify TRF2's mysterious understudy, Markiewicz-Potoczny analyzed thousands of mouse embryonic stem cells with a tool called CRISPR-Cas9. She focused on the cells that continued to thrive despite the absence of TRF2.

The researchers eliminated genes from each cell, one by one. When the cells began degrading, that meant they'd singled out the gene that was protecting the telomeres. Sure enough, the TRF2-deficient cells only became dysfunctional when the researchers removed a specific set of molecules: the ones comprising a pathway called nonsense-mediated mRNA decay, or NMD.

Without the NMD pathway, TRF2-deficient cells died, and chromosomal telomeres degraded. Their frayed ends started fusing with those of nearby chromosomes.

Toward healthy aging and cancer care

Scientists first discovered the NMD pathway in 1979. At that time, they classified the pathway as an internal surveillance mechanism. Its primary function is to find and delete problematic (or "nonsense") RNA sequences.

Markiewicz-Potoczny's paper added a new function to the pathway's repertoire: Because of its critical role in preserving telomeres, the pathway might be used to reverse age-related telomere degradation and boost cell health throughout the lifespan. In cells that are already cancerous, sabotaging the NMD pathway could help prevent the disease from spreading.

"I'm excited to investigate NMD further to evaluate its value to both cancer prevention and healthy aging," Markiewicz-Potoczny said. "I am so lucky to do this work."