Two-faced codon rewrites genetics?

The genetics of a marine protozoan may overturn one of the long-held tenets of protein synthesis. According to conventional wisdom, the genetic code is unambiguous: each DNA triplet, or codon, corresponds to a single amino acid. But a linkurl:study;http://www.sciencemag.org/cgi/content/abstract/323/5911/25 in this week's __Science__ reports that in the wee waterborn creature __Euplotes crassus__, a single codon can code for two different amino acids, even within the same gene. This two-pronged

By | January 8, 2009

The genetics of a marine protozoan may overturn one of the long-held tenets of protein synthesis. According to conventional wisdom, the genetic code is unambiguous: each DNA triplet, or codon, corresponds to a single amino acid. But a linkurl:study;http://www.sciencemag.org/cgi/content/abstract/323/5911/25 in this week's __Science__ reports that in the wee waterborn creature __Euplotes crassus__, a single codon can code for two different amino acids, even within the same gene. This two-pronged coding could be a universal feature of all domains of life, said linkurl:Vadim Gladyshev,;http://genomics.unl.edu/gladyshev/ a biochemist at the University of Nebraska in Lincoln, who led the study. "__Euplotes__ is just one example, but the implications are that this situation [one codon coding for two amino acids] might exist in other organisms," he told __The Scientist__. "If __Euplotes__ can use a codon for targeted and specific insertion of two amino acids into different positions in a protein, why not other organisms, too?" The universal genetic code generally encodes the same 20 amino acids and three stop signals in all organisms, although a small number of genes in many organisms, including humans, contain two additional amino acids -- selenocysteine and pyrrolysine. What's more, some species and organelles use alternative genetic codes, including many protists that rewire certain triplets that normally code for stop codons to code for specific amino acids instead. __Euplotes crassus__ is a tiny, marine ciliate -- about the size of the width of a human hair -- that does both of these things simultaneously, the new study reports. In __E. crassus__, the UGA triplet, which is a stop codon in most eukaryotes, codes for both cysteine and selenocysteine.

**Differential interference contrast micrograph of __E. crassus__.**

Gladyshev and his colleagues analyzed the __E. crassus__ genome sequence and found eight genes for proteins that incorporate selenocysteine, four of which contained multiple UGA codons. By expressing these genes in human embryonic kidney cells and using mass spectrometry on the __E. crassus__ proteins, Gladyshev's team showed that UGA differentially coded for either cysteine or selenocysteine. They also found that which amino acid was incorporated into the protein depended on the proximity of the UGA codon to a specific structure in the 3' untranslated region called the "Sec insertion sequence," or SECIS. linkurl:John Atkins,;http://www.bioscience.utah.edu/mb/mbFaculty/atkins/atkins.html a molecular biologist at the University of Utah in Salt Lake City and University College Cork in Ireland, who was not involved in the study, said that dual coding might be a "specialist situation," rather than a general phenomenon. Still, the observation that the SECIS element was differentially affecting the ribosome at various UGA triplets has major mechanistic implications about the fine-tuned control of ribosome-based protein synthesis, he said. "It shows that there must be very specialized folding of RNA in the 3' untranslated region to talk to the ribosome," he told __The Scientist__. "The redefinition [caused by SECIS] is not of the ribosome as a whole; rather, the signal is determining a localized definition." But the paper's findings might not be all that novel, cautioned Yale University microbiologist Dieter Söll. He noted that in some __Candida__ species, the CUG codon is translated as both leucine and serine, even in the same gene, albeit by a single ambiguous tRNA rather than two separate tRNAs as Gladyshev's team found in __E. crassus__. "This already showed that you can have the same codon in one gene [encode] two amino acids," Söll told __The Scientist__. "Really, it simply shows that nature has more than one way of doing the same thing." Gladyshev disagrees. "It's really a completely different situation," he said. In __Candida__, the tRNA doesn't discriminate between amino acids, he noted. Rather, it randomly inserts either serine or leucine, "whereas in our case there is a specific insertion of one amino acid or the other, depending on the presence and availability of the RNA element." Söll also noticed a technical error in the paper. In Figure 2, the putative cysteine tRNA that Gladyshev identified from the genome sequence had a cytosine residue at a terminal "charging site." But all other known cysteine tRNAs have uracil instead, Söll noted. Gladyshev said the figure contained a mistake: the true nucleotide was, indeed, a uracil. "I would like to thank... the expert who noticed this," he wrote in an email. The sequence he submitted to Genbank was correct, he noted, and he has contacted __Science__'s editors to issue a correction. Gladyshev is now searching for other organisms that display dual coding. He is also investigating mammalian selenocysteine-containing genes to investigate whether the position of the SECIS element affects the incorporation of selenocysteine at different codon sites. __Image courtesy of Lawrence Klobutcher
**Related stories:__***linkurl:Nirenberg's genetic code chart, 1961-66;http://www.the-scientist.com/2007/6/1/88/1/
[June 2007]*linkurl:Extending the genetic code;http://www.the-scientist.com/article/display/21537/
[15th August 2003]*linkurl:And then there were 22;http://www.the-scientist.com/article/display/20435/
[7th June 2002]

Comments

January 9, 2009

I was wondering how would this surprising finding, if verified in other organisms (human?), impact our current understanding of the sequenced (human) genome(s)
Avatar of: anonymous poster

anonymous poster

Posts: 107

January 10, 2009

You do your readers a disservice with sensationalistic and misleading headlines like "rewrites genetics", even with a question mark tacked on. This report has next to zero impact on genetics and isn't even that novel; the molecular biology of selenocysteine is taught in most introductory biochemistry courses.\n\nResearchers in pursuit of funding may be forgiven for making grandiose claims about the significance of their work. It's the job of editors to exercise more sober judgement. Yours were asleep at the switch.

January 11, 2009

I've been teaching this (selenocysteine and pyrrolysine usage of stop codons) at undergraduate level for several years now. There has been several reviews on the subject in the past few years, including on the difference on SECIS sequences in eucaryotes and the role of the sel operon in procaryotes. Same thing for pyrrolysine incorporation at UAG codons downstream of PYLIS sequences.\nWhere's the news ? Where's the revolution in genetics ?\nAin't there enough true discoveries being made lately?
Avatar of: Matthew Grossman

Matthew Grossman

Posts: 27

January 11, 2009

Let us not forget it has long been known and is fairly common that in some prokaryotes various codons are used to encode for Methionine as the start codon, primarily ATG which otherwise codes for Methionine, GTG which otherwise codes for Valine and TTG which otherwise codes for Leucine. In the case the situation is analogous with one codon encoding for two different amino acids within the same gene. However the positional context is different and therefore the situation in Euplotes crassus appears different but may use a related mechanism.\n\nAlso Suppressor tRNAs, witch insert, for instance tyrosine, for the UAG stop codon, and other suppressor tRNAs are also well known. In this case a mutant tRNA is responsible.

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