Study shows how gene related to Nascimento Syndrome activates the cell response to stress

According to a Duke University study published May 24th in the journal Cell Reports, a gene linked to severe learning disabilities in humans also plays a critical role in cells’ response to environmental stress.

Study shows how gene related to Nascimento Syndrome activates the cell response to stress
Like superheroes of the cell, the protein Rad6 (red), and its partner Uba1 (blue) respond to environmental stress by modifying the protein-producing ribosomes (purple) to stop their maintenance program. Image Credit: Dinachi Okonkwo.

Factors that can harm cells, such as excessive temperatures, poisonous chemicals, or mechanical shocks, put them under stress. They go through a series of molecular changes known as the cellular stress response when this happens.

Every cell, no matter from which organism, is always exposed to harmful substances in their environment that they have to deal with all the time. Many human diseases are caused by cells not being able to cope with these aggressions.”

Gustavo Silva, Study Senior Author and Assistant Professor, Biology, Duke University

During the stress response, cells turn on genes associated with crisis mode and turn off genes associated with routine housekeeping functions. They put down the window cleaner, turn off the TV, and rush to close the windows, then patch holes, turn on the sump pump, and, if necessary, pull up carpet and toss away irreversibly ruined furniture, just like they would in a flooded house.

The scientists discovered that a collection of proteins inside the cells were being transformed under stress while examining pathways connected to cell health and response to stress. They dug further and discovered that a gene called Rad6 is the primary regulator of this process.

When there is a stressor, cells need to change what proteins are produced. Rad6 goes in and gets the (protein-building) ribosomes to change their program and adapt what they are producing for the new stressful circumstances.”

Vanessa Simões, Study Lead Author and Research Associate, Silva Lab, Duke University

Rad6 is not an average gene. It can be present in virtually all multicellular creatures, sometimes under a different name. It is recognized in humans for being linked to a cluster of symptoms known as “Nascimento Syndrome,” which includes severe learning disabilities.

Nascimento Syndrome, also known as X-linked intellectual disability type Nascimento, is a disease that has yet to be fully characterized. It was first identified in 2006, and it tends to run in families, providing scientists with an early indication of its genetic causes. Affected people have significant learning disabilities, as well as distinctive facial features such as wide-set eyes and a depressed nasal bridge, as well as a variety of other debilitating symptoms.

Rad6, like many other genes, has several functions. It is a powerful device. Silva and their research colleagues have added a new piece to the puzzle of Nascimento Syndrome by uncovering an extra function that is so closely tied to the cell’s health.

It’s still a big question or how exactly can a mutation to this gene lead to such a drastic syndrome in humans. Our findings are exciting because Rad6 can be a model on which we can do genetic manipulations to try to understand how problems in coping with harmful conditions can be connected to how this disease progresses.”

Gustavo Silva, Study Senior Author and Assistant Professor, Biology, Duke University

If we get a better understanding of how this gene works, we can actually try to interfere with it to help these patients have a better outcome,” Silva added.

But how can one “look” at what happens when a cell is stressed with an infinitesimally little protein? With a fair amount of collaboration, Simões and Silva teamed together with Duke Biochemistry and Pratt School of Engineering experts to get all of the aid they needed.

We used biochemistry analyses, cellular assays, proteomics, molecular modeling, cryo-electron microscopy, a whole set of advanced techniques. It’s the cool thing about being in a place like Duke. We found collaborators and resources easily, right here, and that really increases the impact of a study and our ability to do a more complete work,” Silva concluded.

Source:
Journal reference:

Simões, V., et al. (2022) Redox-sensitive E2 Rad6 controls cellular response to oxidative stress via K63-linked ubiquitination of ribosomes. Cell Reports. doi.org/10.1016/j.celrep.2022.110860.

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