13 July

Translation stimulates regulation of an mRNA by small RNAs

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Researchers from the group of Marvin Tanenbaum have found that regulation of gene expression by small RNAs depends on translation itself. For the first time they were able to look at this process in living cells under the microscope and found that active translation of an mRNA molecule by at least one ribosome stimulates binding of a small RNA and subsequent regulating of the mRNA. The results of this study were published in Nature Structural and Molecular Biology on July 13th.

From gene to protein
Even though cells in the body have different functions, each cell contains the same DNA. The different functions are determined by the genes in the DNA that are active, and which are not. For active genes to perform their function, they are first copied into molecules called mRNAs, which can leave the nucleus of a cell and go into the cytoplasm. Once in the cytoplasm, the mRNA molecules are translated into proteins by ribosomes, small mobile factories that can run along the mRNA molecule and read and translate the genetic code.

Small RNAs
During this sequence of processes, from DNA to protein, there are many ways in which the activity of a gene, or the expression level, can be regulated. There is regulation at the level of the DNA, the mRNA and the protein. Small RNAs are molecules that can regulate gene expression at the level of the mRNA. Some of these small RNAs recognize specific mRNAs and bind to them, subsequently inhibiting translation, or cut the mRNA in two, initiating its breakdown. Small RNAs are mis-regulated in a variety of diseases, so understanding how they work may help us better understand these diseases.

Ball of spaghetti
Suzan Ruijtenberg and Stijn Sonneveld, researchers in the group of Marvin Tanenbaum, have now found translation of the mRNA itself affects whether small RNAs can bind to the mRNA and decrease gene expression. “To understand why this is, you should realize that the long molecules of mRNA in the cell form structures that resemble a ball of spaghetti”, says Sonneveld. This makes it a lot more difficult for a small RNA to recognize the mRNA – the recognition site may be hidden inside the ball of spaghetti. Only when a ribosome is translating the mRNA, the spaghetti is unwound into a long strand. This long strand can be recognized by small RNAs, which can result in an inhibition of gene expression.

One single ribosome
Ruijtenberg and Sonneveld were able to visualize this process in live cells for the first time at the single molecule level, which made it possible for them to conclude that translation of an mRNA stimulates binding of small RNAs to that mRNA, and subsequent cutting of that mRNA in two pieces. “We are especially proud that we could also show that one single ribosome is enough to unwind the mRNA and let the small RNA bind and cut the mRNA”, says Ruijtenberg. They saw that the mRNA is only cut into two pieces, once the ribosome is either very close to or has passed the recognition site of the small RNA.

Some small RNAs are also used in therapy. A better understanding of how these molecules work may also help improve these therapies.

Translation of a single mRNA molecule, both with and with a small RNA present. When a small RNA is present, the mRNA molecule is cut into two pieces (green and purple) while it's translated.

mRNA structural dynamics shape Argonaute-target interactions. Suzan Ruijtenberg*, Stijn Sonneveld*, Tao Ju Cui, Ive Logister, Dion de Steenwinkel, Yao Xiao, Ian J. MacRae, Chirlmin Joo, Marvin E. Tanenbaum. Nature Structural and Molecular Biology 2020.
* these authors contributed equally

Suzan Ruijtenberg did her postdoctoral research in the group of Marvin Tanenbaum and has recently started her own research group as an assistant professor at Utrecht University, studying the importance of translation regulation during development.

Stijn Sonneveld is doing his PhD research in the group of Marvin Tanenbaum.

Marvin Tanenbaum is group leader at the Hubrecht Institute and Oncode Investigator.