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All living things use the genetic code to "translate" DNA-based genetic information into proteins, which are the main molecules working in cells.
Precisely how the complex process of translation appeared in the early stages of life on Earth. More than four billion years ago has long been mysterious, but two theoretical biologists have now made a significant advance in solving this mystery.
Charles Carter, PhD, professor of biochemistry and biophysics at the UNC School of Medicine, and Peter Wills, PhD, an associate professor of biochemistry at the University of Auckland, used advanced statistical methods to analyze how modern translational molecules integrate to accomplish their work – linking short sequences of genetic information to the building blocks of protein that they encode.
Analysis, published in Nucleic Acids Research reveals previously hidden rules by which key translation molecules interact today. Research suggests how the much simpler ancestors of these molecules began to work together at the dawn of life.
"I think we have clarified the underlying rules and evolutionary history of genetic coding," Carter said. "It has not been solved for 60 years."
Wills added: "The pairs of molecular models we have identified are the first that nature has ever used to transfer information from one form to another in living organisms."
The findings focus on a clover-shaped molecule RNA (tRNA), a key player in translation. A tRNA is designed to carry a simple protein building block, known as an amino acid, on the assembly line of protein production within tiny molecular factories called ribosomes. When a copy or "transcription" of a gene called messenger RNA (mRNA) emerges from the nucleus of the cell and enters a ribosome, it is bound to tRNAs carrying their amino acid cargoes.
The mRNA is essentially a chain of genes "letters" stating instructions for making proteins, and each tRNA recognizes a specific sequence of three letters on the mRNA. This sequence is called a "codon". As the tRNA binds to the codon, the ribosome binds its amino acid to the amino acid that preceded it, lengthening the growing peptide. Once completed, the amino acid chain is released as a newly born protein.
Proteins in humans and most other life forms are made from 20 different amino acids. Thus, there are 20 distinct types of tRNA molecules, each capable of binding to a particular amino acid. In partnership with these 20 tRNAs, 20 auxiliary enzymes called synthetases (aminoacyl-tRNA synthetases), whose job is to load their tRNA partners with the correct amino acid.
"You can think of these 20 synthetases and 20 tRNAs collectively as a molecular computer that evolution designed to do gene translation to protein," Carter said.
Biologists have long been intrigued by this molecular computer and the puzzle of how it appeared billions of years ago. In recent years, Carter and Wills have made this puzzle their main research center. They have shown, for example, how the synthetases, which exist in two structurally distinct classes of synthetases, probably originated from two simpler ancestral enzymes.
A similar class division exists for amino acids, and Carter and Wills have argued that the same class division must apply to tRNAs. In other words, they propose that at the dawn of life on Earth, organisms contained only two types of tRNA, which would have worked with two types of synthetases to perform a translation from gene to protein using only two different types of amino acids. 19659003] The idea is that over the centuries this system has become more and more specific because each of the original tRNAs, synthetases and amino acids has been augmented or refined by new variants up to that there are separate classes of 10 in place of each of the two original tRNAs, synthetases and amino acids.
In their most recent study, Carter and Wills examined modern tRNAs in search of this ancient duality. To do this, they analyzed the top of the tRNA molecule, known as the acceptor stem, where the partner synthetases bind. Their analysis showed that only three RNA bases, or letters, at the top of the acceptor stem carry an otherwise hidden code specifying rules that divide the tRNAs into two classes – corresponding exactly to the two classes of synthetases. "It's just the combinations of these three bases that determine which class of synthetase binds to each tRNA," Carter said.
The study accidentally found another proposal for tRNAs. Each modern tRNA has at its lower end an "anticodon" that it uses to recognize and stick to a complementary codon on an mRNA. The anticodon is relatively far from the synthetase binding site, but scientists since the early 1990s speculated that tRNAs were once much smaller, combining the anticodon and synthetase binding regions into one. The analysis of Wills and Carter shows that the rules associated with one of the three bases determining the class – the number 2 base in the overall molecule of tRNAs – actually imply a trace of the l / 3. anticodon in an old truncated version of tRNA
These results reinforce the argument that the original translation system had only two primitive tRNAs, corresponding to two synthetases and two types of amino acids. As this system evolved to recognize and incorporate new amino acids, new combinations of tRNA bases in the synthetase binding region would have appeared to follow increasing complexity – but in a way that left detectable traces of the original arrangement
. "These three bases defining the class in contemporary tRNAs are like a medieval manuscript whose original texts have been erased and replaced by more recent texts," Carter said.
The results narrow the possibilities of genetic coding. In addition, they restrict the scope of future experiments that scientists could undertake to reconstruct early versions of the laboratory translation system – and perhaps even evolve this simple system into more complex and modern forms of the same translation system. It would show how life evolved from the simplest of molecules to complex cells and organisms
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Header Image – At first, the genetic bases were translated into proteins to lead to complex life as we know it. Credit: Christ-claude Mowandza-ndinga
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