Stress affects cell division. Previous studies have shown high levels of stress can damage cells in the human body. If these damaged cells undergo cell division, the new cells will also be damaged. Now, researchers at UT Southwestern (UTSW) report they have identified a protein that can stop the cell cycle in response to stressful events.

Their findings are published in the Journal of Cell Biology, in a paper titled, “Cell cycle–independent integration of stress signals by Xbp1 promotes Non-G1/G0 quiescence entry.”

“Cellular quiescence is a nonproliferative state required for cell survival under stress and during development,” the researchers wrote. “In most quiescent cells, proliferation is stopped in a reversible state of low Cdk1 kinase activity; in many organisms, however, quiescent states with high-Cdk1 activity can also be established through still uncharacterized stress or developmental mechanisms.”

“Scientists have been studying this fundamental process for nearly seven decades,” said Orlando Argüello-Miranda, PhD, an instructor who co-led the study with assistant professor Jungsik Noh, PhD, both of UTSW’s Lyda Hill department of bioinformatics. “We’ve essentially identified a protein that can stop the cell cycle in response to stressful conditions.”

It has long been known that a stressful event such as starvation can send a cell into a protective state known as quiescence. Typically, the cell cycle halts just before DNA replication takes place, Argüello-Miranda explained. However, a minority of cells seem to become quiescent at other points in the process.

The researchers studied yeast cells challenged by nutritional stress. The researchers were able to study individual cells using a technique called microfluidics six-color imaging, which was developed at UTSW. The technique combines a technology for cell culture called microfluidics with a six-color fluorescent-microscopy approach pioneered at UTSW in 2018.

A microscopy technique created at UT Southwestern and powered by machine learning can detect multiple biochemical reactions in single cells in real time. The study found levels of the Xbp1 protein (green) rise in response to repeated or prolonged stress. Each colored hexagon corresponds to a different biochemical reaction tracked in the cells displayed in the center hexagon. [UT Southwestern Medical Center]
“In previous studies in the field, researchers cultured yeast cells in flasks and were unable to track single cells,” explained Argüello-Miranda. “In contrast, we have obtained movies that record how individual cells stop dividing and enter quiescence.”

Using the new technique, the researchers found that all the starved cells showed elevated levels of a suite of stress response proteins. However, cells that became inactive at unexpected points in the cell cycle all had an abundance of Xbp1, which is needed to stop the cell cycle after DNA replication.

“This accumulation was so predictable we could tell how many stressful events a cell had been exposed to by how much Xbp1 was present in the cell nucleus,” Argüello-Miranda said. The findings suggest that Xbp1 has a newly discovered function in regulating the cell cycle, allowing yeast cells to “remember” exposure to stress and to protect themselves by entering quiescence, he added.