Deep in the protein translation machinery are cogs known as transfer RNAs, or tRNAs. Actually, they may be more than mere cogs, say scientists at the University of Chicago. Like other components of the cell’s protein translation machinery, tRNAs may play an important regulatory role. At least one tRNA, the scientists have discovered, can globally increase or decrease protein synthesis, depending on whether or not it has been demethylated by an enzyme. Now the scientists are eager to explore tRNA’s regulatory potential more deeply.

While it has been understood for some time now that tRNAs are heavily decorated with small molecules such as methyl groups (carbon atoms bound to three hydrogens), the University of Chicago scientists have uncovered something new: one of tRNA’s modifications can be removed by an enzyme called ALKBH1. Absent this modification, tRNAs are degraded by the cell. Moreover, as the scientists report in a new study, the ALKBH1-catalyzed demethylation of the target tRNAs results in attenuated translation initiation and decreased usage of tRNAs in protein synthesis.

These findings appeared October 13 in the journal Cell, in an article entitled, “ALKBH1-Mediated tRNA Demethylation Regulates Translation.” The article shows that mammalian ALKBH1 is a tRNA demethylase. The enzyme mediates the demethylation of N1-methyladenosine (m1A) in tRNAs.

“One salient feature of tRNA is its heavily modified status, which can critically impact its function,” the article’s authors explain. “Our results uncover reversible methylation of tRNA as a new mechanism of post-transcriptional gene expression regulation.”

An especially important tRNA that ALKBH1 acts on is tRNAiMet, a tRNA molecule carrying the amino acid methionine, which initiates translation for all proteins. Thus, high ALKBH1 activity can globally decrease the amount of proteins made in a cell, as the researchers observed in a human cell line with abnormally high levels of ALKBH1.

Not only did these cells have a lower rate of protein synthesis, they also divided less frequently than those with normal or low levels of ALKBH1, suggesting that this enzyme has a powerful effect on cellular health. The researchers also observed that in normal cells, the amount and activity of ALKBH1 varied with environment; cells deprived of energy sources increased ALKBH1 action to conserve resources.

“The ability to reverse something, to remove something, confers the possibility of dynamics,” said Tao Pan, Ph.D., professor of biochemistry and molecular biology at the University of Chicago, and a senior author of the study. “I would say that the ribosome is the hardware of the computer, the messenger RNA is somebody who enters the information to instruct on how to do something, and the tRNA is the software on how to translate that into something. So now we know that the software itself can be tweaked, or modified, or dynamically changed.”

Scientists have discovered many points of regulation in the process of using a specific DNA template to make a protein, known as gene expression, that allow the cell to control how much of a certain protein is made at a certain time. For example, by the 1980s, it was established that the addition or removal of several small molecules to or from DNA could affect gene expression. More recently, work done by Chuan He, Ph.D., professor of chemistry at the University of Chicago and the other senior author of the new study, demonstrated that a similar method of regulation exists for messenger RNA.

The current study, which shows that reversible modifications to tRNA can have a measurable effect on protein translation, points to another mechanism that can influence gene expression. The full implications of the new discovery have yet to be determined

It has been noted by other groups that genetically modified mice lacking ALKBH1 have severe neuronal defects along with other developmental deficiencies, information that takes on new significance now that the function of ALKBH1 has been defined. Dr. He sees two, most likely overlapping, interpretations. One is straightforward—during development, cells are assuming their identities and need precise control over protein production, so cells lacking a gene expression regulation mechanism are bound to have defects, particularly in the case of specialized cells like neurons. The second possibility, namely that tRNA influences processes beyond translation, is perhaps more interesting to both Drs. Pan and He.

“Scientists are starting to realize that there are nontranslational roles for tRNA. This methylation is key for the stability of the tRNA,” noted Dr. He. “The other side of the coin is that demethylation by ALKBH1 could be a way to promote nontranslational roles. This is something we wish to explore in the future.”

In any case, Drs. Pan and He are confident that their work on ALKBH1 will open up a new area of investigation in the study of RNA modifications, and that more enzymes that demodify tRNA will be discovered in the near future. More broadly, this landmark discovery has illuminated an unexplored avenue in scientists' understanding of how cells control gene expression and could incite a fresh wave of innovation in this ever-growing field.

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