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Researchers from UT Southwestern have discovered a mechanism that cells use to degrade microRNAs (miRNAs), genetic molecules that regulate the amount of protein in cells.
The results, reported online today in Science, not only sheds light on the inner workings of cells, but could eventually lead to new ways to fight infectious diseases, cancer and a host of other health problems.
Scientists have long known that genes contain the instructions for making every protein in an organism’s body. However, various processes regulate whether different proteins are produced and in what quantity. One of these mechanisms involves miRNAs – small pieces of genetic material that break down complementary pieces of messenger RNA (mRNA) in cells, preventing the mRNA sequence from being translated into proteins.
Since the discovery of miRNAs in 1993, researchers have accumulated a wealth of knowledge about hundreds of different miRNA molecules and their targets, as well as the mechanisms that control their production, maturation, and roles in development, physiology and disease. However, explains Joshua Mendell, MD, Ph.D., professor and vice president of the molecular biology department at UTSW, and postdoctoral fellow Jaeil Han, Ph.D., very little was known about how cells clear miRNAs when “you’re done using them.
“As long as miRNA molecules remain in a cell, they reduce the production of proteins from their target mRNAs,” explains Mendell, a researcher with the Howard Hughes Medical Institute (HHMI) and a member of the Harold C. Simmons Comprehensive Cancer Center. “So understanding how cells get rid of miRNAs when they are no longer needed is critical to fully appreciating how and when they do their job.”
To answer this question, Mendell, Han and their colleagues leveraged CRISPR-Cas9, a gene editing tool that recently won the 2020 Nobel Prize in Chemistry for two scientists who developed it. By serving as “molecular scissors,” Mendell says, this system can cut through individual genes, allowing researchers to explore their functions.
In a human cancer cell line known as K562, researchers used CRISPR-Cas9 to target most of the 20,000 protein-coding genes in the human genome, looking for those that caused the permanence of a normally short-lived miRNA known as miR-7 cells. Their research revealed at least 10 genes required to degrade this miRNA.
The researchers learned that the proteins encoded by these genes come together in cells to form a larger whole known as a ubiquitin ligase, which functions to label other proteins for destruction. This particular ubiquitin ligase has never been described before, Mendell says, but like other ubiquitin ligase complexes, it appears to mark proteins destined for degradation. However, instead of labeling miR-7 itself, further investigation showed that this complex instead labels a protein called Argonaute, which transports miRNAs through cells.
Once the Argonaute protein attached to miR-7 is targeted for degradation, this miRNA is left bare in the cell, a state that activates the cells to destroy the miRNA using RNA-degrading enzymes.
The research team found that this ubiquitin ligase complex is critical for degrading not only miR-7 in K562 cells, but also a variety of other miRNAs in other cell types and species. These results suggest that this mechanism for miRNA decay acts extensively to control miRNA levels during animal development and through tissues. As other studies have shown that abnormal levels of various miRNAs are associated with a variety of diseases and infections, finding ways to control the degradation of miRNAs – either to eradicate problematic miRNAs in cells or to retain beneficial ones – could represent a new way to treat. this conditions.
“For over a decade, researchers have been looking for mechanisms by which cells degrade miRNAs,” says Han. “Now that we have discovered a new cellular mechanism capable of achieving this, we will be able to apply this discovery to better understand how miRNAs are regulated and hopefully eventually develop new therapies.”
Other UTSW researchers who contributed to this study include Collette A. LaVigne, Benjamin T. Jones, He Zhang, and Frank Gillett.
This study was funded by grants from the National Institutes of Health (R35CA197311, P30CA142543 and P50CA196516), the Welch Foundation (I-1961-20180324), the American Heart Association (19POST34380222), the Cancer Prevention and Research Institute of Texas (RP150596 ) and the HHMI.
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