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Every cell has an entire legion of translators providing their crucial service. The work of these highly specialized molecules must be efficient yet accurate; research shows that they accomplish this partially through teamwork. When one is hurt or needs help, others provide backup. Research at the Weizmann Institute, which was recently reported in eLife, explains how the backup mechanism works, as well as revealing how evolution enables the cell to cope with change. That change may be an alteration in the cell’s environment that necessitates adaptation, or it could be a change in the cell, itself, that turns it cancerous and then induces further modifications in the protein manufacturing process so as to support the cancer growth.
Translation – the second step in the process of transforming the DNA code to protein – involves a conversation between two different chemical languages: the encoded nucleotide argot of the messenger RNA and the amino-acid vernacular of the proteins. The Rosetta Stone of cellular translation is a two-headed molecule called transfer RNA (tRNA). The side that “speaks” nucleotide is called an anticodon; it identifies a single triple-nucleotide sequence in the messenger RNA, called a codon, which encodes a specific amino acid. The other head on the molecule identifies that amino acid. Simple enough, but the translation team works with added layers of complexity. For example, each of the 20 amino acids can be encoded in a number a different codons, each with its own tRNA. And not all tRNA molecules are equal: Some are encoded in a single gene, and are thus rare in the tRNA legions, while others are found in multiple copies.
Prof. Tzachi Pilpel of the Molecular Genetics Department researches the translation system. Several years ago, Zohar Bloom, then a research student in Pilpel’s group, created a “library” of mutated yeast cells, each containing a different mistake in one of the cell’s 274 tRNA genes (as well as some with multiple mutations). In particular, they wanted to see how the cell copes with these potentially damaging mutations, and whether it employs a good backup system.
Their research showed that such a backup does, indeed, exist – one that could be called tinkering. The cell patches together a chemical alteration on a similar tRNA molecule so that it can substitute for the missing one. This quick (and reversible) mechanism keeps the cell alive, but it is imperfect: The growth efficiency of yeast cells with a tRNA mutation was about 90% that of a normal cell.
As a quick fix, the chemical modification could be seen as a relative success, but over time, such yeast cells would lose out in the evolutionary fitness race. Can evolution provide a better, more permanent solution to the loss of a tRNA? Pilpel and his lab group, including research students Avihu Yona, Zohar Bloom-Ackerman, Idan Frumkin, Yoav Charpak-Amikam and research fellow Dr. Orna Dahan had a method to test this question in the lab: test-tube evolution. Yeast cells from the library's collection were grown in a robotic system over a period of weeks or months, allowing them to divide and accumulate further mutations. Continuous analysis of the yeast in this system enabled the researchers to track their evolution in real time.
After a month, one of their strains of yeast gave them a surprise: Its development had improved, and now rivaled that of normal yeast. As to why, the team members had two competing theories, and they began to place bets on the eventual outcome. The first theory stated that the solution to the missing tRNA was in another mutation. The second group thought that the recovery was too quick for a mutation of this sort to have taken effect, and the cell must have better tinkering skills to adapt on the similar molecule.
Common genes and rare ones
To settle the issue, the team sequenced all of the genes that coded for relevant tRNA molecules. The result: Those claiming a genetic mutation won the bet. The mutation was in the anticodon of the gene for a different tRNA that binds to the same amino acid, but with a different codon. This mutation was successful because it was in a gene for a common tRNA – there are normally 11 copies of it in the yeast cell. To exclude the possibility that another backup mechanism was at work, the scientists created yeast cells with two mutations – intentionally creating the mutation they had seen and removing the original tRNA. These yeast grew normally.
That the evolutionary change in these yeast was so rapid as to seem impossible, but a mathematical analysis showed it was actually not too fast to have occurred in a month of evolution. A likely explanation, says Pilpel, is that for these particular cells there is a large selection of available genes – 11. A mutation in any one of them would be sufficient to solve the problem. When the potential backup tRNA molecules are rare, there would be fewer opportunities for beneficial changes to occur.
This raises another question: Why are some tRNAs common and others rare? “Essentially, the question comes down to what the cell profits from having these rare tRNA molecules,” says Pilpel. “The answer we have proposed is that rareness functions as ‘punctuation’ – like a period at the end of a sentence that creates a pause in the flow.” Such pauses are necessary because of protein folding – a process that takes place as translation proceeds. Slowing down translation at various points gives the tricky task of proper folding a chance to catch up. To demonstrate, the scientists added extra copies of these tRNAS to the yeast cells, so they were no longer rare. The result was a complete collapse of the protein folding process. In other words, to work as a team, tRNA molecules need to be available to back up their friends, but also need to know when to make themselves scarce.
Prof. Yitzhak Pilpel's research is supported by the Sharon Zuckerman Laboratory for Research in Systems Biology; the Braginsky Center for the Interface between Science and Humanities; and the European Research Council. Prof. Pilpel is the incumbent of the Ben May Professorial Chair.
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