Surprising Things Lost in Protein Translation

Several years after a perplexing observation in bread mold and more than 50 years after the discovery of DNA, two studies in Nature find that surprising things are lost and found in protein translation.

“Our two studies establish a fundamental and previously unappreciated mechanism in gene and protein regulation that could lead to insights into the causes of genetic disease as well as a better understanding of how organisms adapt to their environment,” said Yi Liu, Ph.D., a Professor of Physiology at UT Southwestern Medical Center.

“We found that less is more in many cases, and the translation process is more complicated than we thought,” he added. Translation is the process through which the genetic information contained in DNA is assembled into proteins, chains of amino acids that carry out cellular processes.

Mian Zhou, Joonseok Cha, Ph.D., Yi Liu, Ph.D.
Mian Zhou, a graduate student, left, Joonseok Cha, Ph.D., and Yi Liu, Ph.D., right, followed an intriguing observation in bread mold to potential new insights into disease-causing mutations.

Dr. Liu is senior author of one study in bread mold and co-author of another done in bacteria that were published together online in February then in the journal’s March 7 print edition. The studies identify a potential new cause of genetic diseases: the speed of protein translation.

“Most human diseases are caused by mutations that affect how proteins function. Previously, people have focused on mutations that affect protein function by changing the sequence of the amino acids that are assembled during the translation process to make each protein. Our studies suggest that ‘silent’ mutations in genetic codons – DNA regions that code for individual amino acids – can affect protein function and result in human disease even when the amino acid sequence remains the same,” Dr. Liu said.

The genetic information in DNA is contained in four nucleotides – represented by the letters A, T, G, and C – that form codons, which are triplets of nucleotides. The four letters can be combined in 64 different ways but there are only 20 commonly used amino acids. That means multiple codons can code for each amino acid, he said.

No Random Process

If the process happened randomly, organisms would use all the codons equally. Instead, most organisms show a bias for certain ones, called optimal or preferred codons. It has long been thought that the bias toward optimal codons existed because those codons sped up protein translation, he explained.

Seven years ago, Dr. Liu’s laboratory decided to compare optimal and non-optimal codons by substituting optimal codons for non-optimal ones in the frequency gene in bread mold, a common fungus. That gene is part of mold’s circadian clock system and naturally contains a high number of non-optimal codons.

They found that substituting optimal codons did accelerate protein translation, as expected, but the clock protein stopped working. That was unexpected because the optimized codons translated into proteins with the same amino acid sequence, he explained.

They further discovered that accelerated protein translation caused the protein to misfold during the translation process, indicating that in addition to specifying a protein’s sequence, gene codons also affect the protein’s shape, which can impair protein function, he said.

Tested in Blue-Green Algae

Dr. Liu then collaborated with Carl Johnson, Ph.D., a Professor of Biological Sciences at Vanderbilt University, to see if the bread mold finding persisted across species by repeating the experiment in blue-green algae, a bacteria that has a 24-hour cycle similar to the biological clocks in bread mold, mice, and humans, he said.

The researchers found that after the bacterial clock’s genetic codons were optimized, the cell was less able to adapt to certain temperatures and cell survival was impaired, he said.

Dr. Liu concludes that the presence or absence of optimized codons affects how much of a protein is made and the structure of that protein. “Many of these ‘silent’ mutations are found in the human genome. Our study indicates a new venue for discovering disease-causing mutations,” he said.

Certain regions of the protein are translated quickly by having optimal codons and other regions of the protein are translated slowly via non-optimal codons. It appears that the right translation speed at the right time is crucial for proper protein function, he said.
“Our studies establish a new role for genetic codons, it’s not just the amino acid sequence anymore,” Dr. Liu said.

Other UTSW authors in the first study include: lead author Mian Zhou, a graduate student of Physiology in the integrative biology program; Jinhu Guo, Ph.D., a former postdoctoral researcher and fellow in Physiology now an independent investigator at the Sun Yat-sen University in China; Joonseok Cha, Ph.D., an Instructor of Physiology; and Michael Chae, Ph.D., a former postdoctoral fellow in Physiology. Other researchers on that study include: She Che, Ph.D., of the National Institute of Biological Sciences, Beijing, China; Jose M. Barral, M.D., Ph.D., of the UT Medical Branch, Galveston, Texas; and Matthew Sachs, Ph.D, of Texas A&M University.

The study in bread mold was funded by the National Institutes of Health and the Welch Foundation.

The bacteria study was funded by the National Institute of Science, the Welch foundation, the National Science Foundation, and the Searle Scholars Program.