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'Master key' microRNA has links to both ASD and schizophrenia

Recent studies of complex brain disorders such as schizophrenia and autism spectrum disorder (ASD) have identified a few "master keys," risk genes that sit at the center of a network of genes important for brain function. Researchers at Emory and the Chinese Academy of Sciences have created mice partially lacking one of those master keys, called MIR-137, and have used them to identify an angle on potential treatments for ASD. The results were published this Read more

synthetic biology

Tracking a frameshift through the ribosome

Ribosomes, the factories that assemble proteins in cells, read three letters of messenger RNA at a time. Occasionally, the ribosome can bend its rules, and read either two or four nucleotides, altering how downstream information is read: frameshifting.

This week, Christine Dunham’s lab in the Department of Biochemistry has a paper in PNAS on how ribosomal frameshifting works, one of several she has published on this topic. The first author is postdoc Samuel Hong, now at MD Anderson. A commentary in PNAS calls their paper a “major advance” and “culmination of a half-century quest.”

A suppressor tRNA can occupy more than one site on the ribosome. Adapted figure courtesy of Christine Dunham

Some antibiotics disrupt protein synthesis by encouraging frameshifting to occur, so a thorough understanding of frameshifting benefits antibiotic research. Also, scientists are aiming to use the process to customize proteins for industrial and pharmaceutical applications, by inserting amino acid building blocks not found in nature.

When mutations add or subtract a letter from a protein-coding gene, that usually turns the rest of the gene to nonsense. Compensatory mutations in the same gene can push the genetic letters back into the correct frame. However, others are separate, found within the machinery for translating the genetic code, namely transfer RNAs: the adaptors that bring amino acids into the ribosome. Suppressor tRNAs can compensate for a forward frameshift in another gene.

The Dunham lab’s new paper solves the structure of a bacterial ribosome undergoing “recoding” influenced by a suppressor tRNA. Her group had previously captured how the ribosomes decode this tRNA in one site of the ribosome, the aminoacyl or A site, in a 2014 PNAS paper. The new structures show how the tRNA moves through the ribosome out-of-frame to recode. The tRNA undergoes unusual rearrangements that cause the ribosome to lose its grip on the mRNA frame and allows the tRNA to form new interactions with the ribosome to shift into a new reading frame.

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A new frame of reference — on ribosome frameshifting

It’s a fundamental rule governing how the genetic code works. Ribosomes, the factories that assemble proteins in all types of living cells, read three letters (or nucleotides) of messenger RNA at a time.

In some instances, the ribosome can bend its rules, and read either two or four nucleotides, altering how downstream information is read. Biologists call this normally rare event ribosomal frameshifting. For an ordinary gene, the event of a frameshift turns the rest of the ensuing protein into nonsense. However, many viruses exploit frameshifting, because they can then have overlapping genes and fit more information into a limited space.

Regulated frameshifting takes place in human genes too, and understanding frameshifting is key to recent efforts to expand the genetic code. Researchers are aiming to use the process to customize proteins for industrial and pharmaceutical applications, by inserting amino acid building blocks not found in nature.

“Going back to the 1960s, when the genetic code was first revealed, there were many studies on ribosomal frameshifting, yet no-one really knows how it works on a molecular and mechanistic level,” says Christine Dunham, PhD, assistant professor of biochemistry at Emory University School of Medicine. “What we do know is that the ‘yardstick’ model that appears in a lot of textbooks, saying that the anticodon loop dictates the number of nucleotides decoded, while elegant, is probably incorrect.”

Dunham, who first studied the topic as a postdoc, and her colleagues published a paper this week in PNAS where they outline a model for how ribosomal frameshifting occurs, based on structural studies of the ribosome interacting with some of its helper machinery. Co-first authors of the paper are postdoctoral fellows Tatsuya Maehigashi, PhD and Jack Dunkle, PhD.

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