A newly revealed molecular tug-of-war may have implications for better understanding how a multitude of diseases and disorders - including cancers, neurodegenerative diseases and immune disorders - originate, as well as how to potentially treat them, according to researchers at Penn State. The team made the finding in a study of cellular messengers called mRNAs that carry the DNA blueprints needed to make proteins, the building blocks of life that keep cells functioning. After delivering the instructions, the messengers are cleared out by a protein complex called CCR4-NOT. The proteins in CCR4-NOT were thought to operate in harmony, but the researchers said that's not the case: one protein destabilizes mRNA while the other steadies it.
The team made the revelation in human colorectal cancer cells with a tool to precisely and temporarily turn off specifically targeted proteins. By essentially removing one protein, called CNOT1, CCR4-NOT slowed mRNA removal, but eliminating another protein from the cell, CNOT4, increased the clean-up process. Details of the tool and their analyses are available online now ahead of publication in an upcoming issue of the Journal of Biological Chemistry.
"Traditionally, subunits are expected to work together toward a common function, but our results show that CNOT4 has unique roles beyond RNA degradation or catalysis," said first author Shardul Kulkarni, assistant research professor of biochemistry and molecular biology at Penn State. "Our study shows that not all subunits of a 'degradation' complex act the same way - some can have distinct and even opposing roles. Understanding these opposing forces gives us a clearer picture of how cells maintain balanced gene expression and could point to new ways to intervene when that balance is lost."
This balance is critical to gene regulation, which Kulkarni described as a dimmer dial that precisely increases or decreases light to control when, where and how much each gene is used, or how often instructions for specific proteins are carried out. Kulkarni said.
"The study of gene regulation is essential for understanding cellular differentiation, the progression from a single embryonic cell to a multicellular organism, and the mechanisms by which organisms adapt to environmental stimuli," Kulkarni said, explaining that, in health, genes provide the blueprints for every biological component of an organism, including mRNA, but that doesn't mean the process is precisely the same all the time. "Our finding provides more information about how the molecules involved in gene regulation balance or even challenge each other as cells respond to stress, nutrition, temperature and other environmental changes. When that regulatory system fails, it can lead to diseases such as cancer, developmental disorders or metabolic problems."
