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Newfound Genetic Code-in-Code Regulates Stress Response

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There are 64 combinations in the genetic code (43), because there are four bases arranged in threes. Each triplet codon codes for one amino acid, of which there are 20 normally used in proteins. This mismatch of 64 versus 20 has been called degeneracy, and has long been a mystery. Some amino acids have a single codon, but others can be coded by up to six codons. Is this redundancy just a “frozen accident,” as Francis Crick thought? Could there be functional reasons why a gene would specify one codon instead of another?

In the past, we examined growing evidence for function in the degeneracy. Last year we learned that different codons work at different rates, providing a “speed limit” mechanism for protein formation. In 2014, Casey Luskin wrote about how differing codons provide the cell with “translational pausing” that affects folding rates with phenotypic effects. The prior year, we saw that alternate codons have effects on circadian rhythms. In 2011, contributor Jonathan M. discussed additional evidences of fine-tuning in the mismatch. As Luskin said, “The theory of intelligent design predicts that living organisms will be rich in information, and thus it encourages us to seek out new sources of functionally important information in the genome.”

Now we have another fulfillment of that prediction. Research at MIT has found a “Newly discovered genetic code [that] controls bacterial survival during infections” (emphasis added). This code-in-a-code makes use of the redundant codons for signaling bacteria to switch on their stress response strategy: “to enter a dormancy-like state that allows them to survive in hostile environments when deprived of oxygen or nutrients.” The team led by Peter Dedon, a professor of biological engineering at MIT, found this out by working with Mycobacterium bovis.

Basically, the codons affect their corresponding transfer-RNAs (tRNA) in different ways. Notice first how complex the transfer RNA system is:

Once a tRNA molecule is manufactured, it is altered with dozens of different chemical modifications. These modifications are believed to influence how tightly the tRNA anticodon binds to the mRNA codon at the ribosome.

In this study, Dedon and colleagues found that certain tRNA modifications went up dramatically when the bacteria were deprived of oxygen and stopped growing.

Experimenting on the bacterium’s response to anoxic conditions, the researchers wondered if alternate codons made a difference. They knew that “the amino acid threonine can be encoded by ACU, ACC, ACA, or ACG,” so they went hunting for possible connections to the stress response.

One of these modifications was found on the ACG threonine anticodon, so the researchers analyzed the entire genome of Mycobacterium bovis in search of genes that contain high percentages of that ACG codon compared to the other threonine codons. They found that genes with high levels of ACG included a family known as the DosR regulon, which consists of 48 genes that are needed for a cells [sic] to stop growing and survive in a dormancy-like state.

When oxygen is lacking, these bacterial cells begin churning out large quantities of the DosR regulon proteins, while production of proteins from genes containing one of the other codons for threonine drops. The DosR regulon proteins guide the cell into a dormancy-like state by shutting down cell metabolism and halting cell division.

Here, then, is powerful evidence for different effects when the same amino acid is encoded by an alternate codon. The work by Dedon’s team is published in Nature Communications, an open-access journal.

Apparently the ACG codon affects the “wobble” of its corresponding tRNA and how tightly the amino acid is bound. This, in turn, affects the translation efficiency in the ribosome, thus regulating the dosages of protein products. They began to see a method in the madness of degeneracy, evident in the phrase “coordinated system”:

Codon re-engineering of dosR exaggerates hypoxia-induced changes in codon-biased DosR translation, with altered dosR expression revealing unanticipated effects on bacterial survival during hypoxia. These results reveal a coordinated system of tRNA modifications and translation of codon-biased transcripts that enhance expression of stress response proteins in mycobacteria.

In the conclusion, they elaborate on this coordinated system, stating that it represents another genetic code:

There is emerging speculation for the existence of a ‘code of codons’ based on gene-specific codon usage patterns that can regulate translation. Among possible mechanisms linking environmental changes to codon-biased translation, recent studies have shown that the dozens of modified ribonucleosides in tRNA form a dynamic system that responds to cellular stress. We have shown that stress-specific alterations in tRNA wobble modifications, which can expand or limit tRNA decoding capabilities, facilitate decoding of cognate codons that are over- or under-used in mRNAs, which enhances translational elongation and leads to the selective up- and downregulation of the codon-biased genes.

The news report from MIT doesn’t hesitate to call this a “newly discovered genetic code” or “alternate genetic code” with functional significance, constituting “another layer of control, mediated by transfer RNA, that helps cells to rapidly divert resources in emergency situations.” Another biochemist comments on the significance of the discovery:

“The authors present an impressive example of the new, emerging deep biology of transfer RNAs, which translate the genetic code in all living organisms to create proteins,” says Paul Schimmel, a professor of cell and molecular biology at the Scripps Research Institute, who was not involved in the research. “This long-known function was viewed in a simple, straightforward way for decades. They present a powerful, comprehensive analysis to show there are layers and layers, ever deeper, to this function of translation.

That’s right out of intelligent design’s list of predictions. As powerful as the evidence was for design in the genetic code’s translation mechanism mediated by tRNA, it wasn’t powerful enough. Now scientists are beginning to view “layers and layers, ever deeper” in its sophistication. “It is really an alternative genetic code, in which any gene family that is required to change a cell phenotype is enriched with specific codons,” Dedon says. And he believes this is not an isolated case. “The researchers have also seen this phenomenon in other species … and they are now studying it in humans.”

Interested in other recent papers with design implications? Check these out:

Boris Zinshteyn and Rachel Green, writing for Science, think about “When Stop Makes Sense.” They investigate why, contra the “standard” genetic code, “stop codons” sometimes specify amino acids. “The answers to this puzzle,” they say, “may provide insights into translation termination and gene regulation in all eukaryotes.”

Sandra Wolin, writing in the Proceedings of the National Academy of Sciences, investigates RNA modification enzymes that act as chaperones, helping tRNAs fold into the proper shape. “Because nucleotide modifications can also stabilize RNA structure and influence folding pathways,” she says, “it will be both exciting and challenging to tease out the relative contributions of each function and the ways in which the two roles intersect and reinforce each other.”

Image credit: Arron Teo via MIT News Office.