Case Western Reserve Scientists Discover Hidden Meaning and 'Speed Limits' within the Genetic Code

Posted: March 13, 2015 at 6:46 am

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Newswise Case Western Reserve scientists have discovered that speed matters when it comes to how messenger RNA (mRNA) deciphers critical information within the genetic code the complex chain of instructions critical to sustaining life. The investigators findings, which appear in the March 12 journal Cell, give scientists critical new information in determining how best to engage cells to treat illness and, ultimately, keep them from emerging in the first place.

Our discovery is that the genetic code is more complex than we knew, said senior researcher Jeff Coller, PhD, associate professor, Division of General Medical Sciences, and associate director, The Center for RNA Molecular Biology, Case Western Reserve University School of Medicine. With this information, researchers can manipulate the genetic code to achieve more predictable outcomes in an exquisite fashion.

The genetic code is a system of instructions embedded within DNA. The code tells a cell how to generate proteins that control cellular functions. mRNA transmits the instructions from DNA to ribosomes. Ribosomes translate the information contained within the mRNA and produce the instructed protein. The genetic code comprises 61 words, called codons, and a single codon, a sequence of three nucleotides, instructs the ribosome how to build proteins.

The code not only dictates what amino acids are incorporated into proteins, it also tells the cell how fast they should be incorporated. With this information, researchers can manipulate the genetic code to achieve predictable protein levels in an exquisite fashion.

The most significant breakthrough in the Case Western Reserve work is that all of the words, or codons, in the genetic code are deciphered at different rates; some are deciphered rapidly while others are deciphered slowly. The speed of how mRNA decodes its information is the sum of all the codons it contains. This imposed speed limit then ultimately affects the amount of protein produced. Sometimes faster is better to express a high level of protein. Sometimes slower is better to limit the amount protein. Importantly, codons are redundant many of these words mean the same thing.

Coller and colleagues found that each of the codons is recognized differently by a ribosome. Some codons are recognized faster than others, but these differences in speed are tiny. Over the entire span of an mRNA, however, each tiny difference in speed is powerfully additive.

Many codons mean the same thing, but they influence decoding rate differently. Because of this, we can change an mRNA without changing its protein sequence and cause it to be highly expressed or poorly expressed and anywhere in between, he said. We can literally dial up or down protein levels any way we want now that we know this information.

During their research, investigators measured the mRNA decay rate for every transcript within the cell. They were seeking answers for why different RNAs had different stabilities. With statistical analysis, investigators compared the half-lives of mRNAs to the codons used within these messages. A strong correlation emerged between codon identity and mRNA message stability. They ultimately linked these observations back to the process of mRNA translation.

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Case Western Reserve Scientists Discover Hidden Meaning and 'Speed Limits' within the Genetic Code

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