A gene linked to severe learning disabilities in humans has also been shown to play a vital role in cells’ response to environmental stress, according to a Duke University study appearing May 24 in the journal. Cell reports.
Cells are stressed by factors that can damage them, such as extreme temperatures, toxic substances or mechanical shock. When this happens, they undergo a series of molecular changes called the cellular stress response.
Every cell, of whatever organism, is always exposed to harmful substances in their environment that they constantly have to deal with. Many human diseases are caused by cells not being able to handle these aggressions.”
Gustavo Silva, assistant professor of biology at Duke and senior author on the paper
During the stress response, cells press to pause genes related to their normal household activities and turn on genes related to crisis mode. Like in a flooded house, they put down the window cleaner, turn off the TV and run to close the windows, then drill holes, turn on the sump pump, and if necessary, tear the carpet open and throw it damaged beyond repair road furniture.
While studying mechanisms related to the health of the cells and their response to stress, the team noticed that a group of proteins in the cells was altered under stress. They dug in and found that the master regulator of this process is a gene called Rad6.
“When there is a stressor, cells have to change which proteins are produced,” said Vanessa Simões, research associate in the Silva lab and lead author of the paper. “Rad6 goes in and causes the (protein building) ribosomes to change their program and adjust what they produce for the new stressful conditions.”
Rad6 is not just any random gene. It occurs, sometimes under a different name, in almost all multicellular organisms. In humans, it is known for its association with a range of symptoms called “Nascimento syndrome,” including severe learning disabilities.
Nascimento syndrome, also called X-linked intellectual disability type Nascimento, is still a poorly understood disease. It was officially described in 2006 and tends to run in families, giving scientists an early clue as to its genetic causes. Affected individuals have severe learning disabilities, distinctive facial features, wide-set eyes and a depressed bridge of the nose, and a range of other debilitating symptoms.
Like many other genes, Rad6 doesn’t do just one thing. It is a multifunctional tool. By discovering an additional function so closely related to cell health, Silva and his team can add another piece to the puzzle of Nascimento syndrome.
“It’s still a big question of how exactly a mutation in this gene could lead to such a drastic syndrome in humans,” Silva said. “Our findings are exciting because Rad6 could be a model where we can do genetic manipulations to try to understand how difficulties coping with harmful conditions might be related to how this disease progresses.”
“As we get a better understanding of how this gene works, we can try to disrupt it to help these patients get a better outcome.” he said.
But how do you actually ‘look’ at what happens to an infinitesimally small protein when a cell is under stress? With a decent dose of teamwork. Simões and Silva teamed up with researchers from the Duke Biochemistry Department and the Pratt School of Engineering to gather all the help they needed.
“We used biochemical analyses, cellular assays, proteomics, molecular modeling, cryoelectron microscopy, a whole host of advanced techniques,” Silva said.
“It’s so cool to be in a place like Duke,” he said. “We found staff and resources here easily, and that really magnifies the impact of an investigation and our ability to do a more complete job.”
Simões, V., et al. (2022) Redox-sensitive E2 Rad6 regulates the cellular response to oxidative stress via K63-linked ubiquitination of ribosomes. Cell reports. doi.org/10.1016/j.celrep.2022.110860.