According to a Duke University study published May 24 in the journal Cell reports.
Cells are stressed by factors that can damage them, such as extreme temperatures, toxic substances or mechanical shocks. When this happens, they undergo a series of molecular changes called the cellular stress response.
“Every cell, regardless of its organism, is always exposed to harmful substances in its environment that it must constantly deal with,” said Gustavo Silva, assistant professor of biology at Duke and lead author of the paper. “Many human diseases are caused by cells that are unable to cope with these attacks.”
During the stress response, cells press-pause genes related to their normal household activities and turn on genes related to seizure mode. Just like in a flooded house, they put down the window cleaner, turn off the television and run to close the windows, then they plug the holes, turn on the sump pump and, if necessary, rip up the carpet and throw it away damaged beyond repair. furniture.
By studying mechanisms related to cell health and their response to stress, the team found that under stress, a group of proteins change inside cells. They dug in and discovered that the master regulator of this process is a gene called Rad6.
“When there is a stressor, the cells have to change the proteins produced,” said Vanessa Simões, research associate at the Silva lab and lead author of the paper. “Rad6 comes in and tells the ribosomes (which make proteins) to change their program and adapt what they produce to the new stressful circumstances.”
Rad6 is not just any random gene. It is found, sometimes under a different name, in almost all multicellular organisms. In humans, it is known to be associated with a cluster of symptoms called “Nascimento syndrome”, which includes severe learning disabilities.
Nascimento syndrome, also called Nascimento-type X-linked intellectual disability, is still a poorly understood condition. It was officially described in 2006 and tends to run in families, giving scientists an early clue to its genetic causes. Affected individuals have severe learning disabilities, characteristic facial features, wide-set eyes and a depressed nose bridge, as well as a range of other debilitating symptoms.
Like many other genes, Rad6 doesn’t just do one thing. It is a multi-purpose tool. By discovering an additional function, closely linked to the health of the cell, Silva and his team manage to add a new piece to the puzzle of Nascimento syndrome.
“It’s still a big question or how exactly can a mutation in this gene lead to such a drastic syndrome in humans,” Silva said. “Our findings are exciting because Rad6 may be a model on which we can genetically manipulate to try to understand how problems managing harmful conditions may be linked to the progression of this disease.”
“If we get a better understanding of how this gene works, we can actually try to interfere with it to help these patients have better outcomes.” he said.
But how do you actually “look” at what is happening with an infinitely small protein when a cell is stressed? With good 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 analysis, cell analysis, proteomics, molecular modeling, cryo-electron microscopy, a whole set of advanced techniques,” Silva said.
“It’s cool to be in a place like Duke,” he said. “We found collaborators and resources easily, right here, and that really increases the impact of a study and our ability to do more comprehensive work.”
Funding for this study was provided by the US National Institutes of Health R00 Award ES025835 and R35 Award GM137954 to Gustavo Silva. This work was also supported in part by R01 Award GM141223 to Alberto Bartesaghi and the NIH Intramural Research Program, National Institute of Environmental Health Sciences Grant ZIC ES103326 to Mario J. Borgnia. The Cryo-EM work was performed at the Duke University Shared Materials Instrumentation Facility (SMIF), a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), which is supported by the National Science Foundation (ECCS-1542015 grant) under the Infrastructure National Nanotechnology Coordinate (NNCI). Funding was also provided by the UNC Lineberger Comprehensive Cancer Center through the University of California, Riverside Fund, and Cancer Center Support Grant P30CA016086.