Fruit fly research conducted at the University of California-Merced has uncovered a cellular process common to many organisms that could significantly impact cancer and aging. The paper published in the journal Nature Communications describes the discovery of a mechanism that cells use to decide how much protein they make through the process of translating RNA into protein.
“This mechanism may be responsible for changes in protein translation in stress, cancer, and aging,” said Department of Molecular and Cell Biology Professor Fred Wolf.
Drosophila in research
Wolf’s lab typically focuses on understanding the brain circuits and genes that control animal behavior. His lab uses Drosophila, a popular choice among researchers because they are inexpensive to work with, reproduce quickly and abundantly and it is easy to alter their genetics to test ideas. Research centered on the fruit fly has led to many sophisticated tools, Wolf said. This is why Genentech Vice President and Senior Fellow in Physiological Chemistry and Research Biology Vishva Dixit, called on Wolf to help understand the function of the protein OTUD6.
“He asked us to use the awesome power of the fly model to discover its function, and we took up the challenge,” Wolf said. “Vishva granted me seed funding to start generating flies with mutations in OTUD6 and testing the mutant flies for any problems they might have. The project really got going when the paper’s first author, Sammy Villa, joined my lab in 2018. Sammy took on the project and his skills in molecular biology and biochemistry were instrumental to the success of the project.”
Potential for stress response, longevity, and cancer cell growth research
In the beginning, the team did not know exactly what they were looking for, so they created flies that were mutant for OTUD6 expecting to find something obvious. However, there were no abnormalities and the flies appeared to be normal.
“We stressed the flies in as many ways as we could conceive of and found they were susceptible to chemical stress, for example, oxidative stress,” Wolf said. “This allowed us to search for how OTUD6 contributed to resilience to stress.”
Then looking for any proteins that were interacting with OTUD6 to discover what it does, the team found that it reduced the ribosomes’ protein production by half. This modification lets cells produce more protein, this is important because the amount of protein generated can have a significant impact on some types of cancers.
“We were quite surprised by the huge impact OTUD6 had on how much protein was made in cells: Making flies mutant for OTUD6 cut protein production in half. That’s a big difference,” Wolf said. “The amount of protein produced in cells is known to affect how long animals live, with less protein being made correlating with longer lifespan. Our OTUD6 mutants lived twice as long. We think this is because there is less protein being made.”
In many cancers, the levels of OTUD6 are increased, and many cancers also have increased protein production. Although they don’t have any direct evidence yet, however, increased OTUD6 may contribute to cancer cell growth and proliferation.
Cells can change their amount of OTUD6 to change how much protein is made. The team wants to continue investigating how cells change the amount of OTUD6 they have, to examine how the pathway is initiated which could reveal ways of manipulating protein production to have positive effects on longevity and cancer outcomes.
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