A Hidden Layer in Your DNA Is Running Your Body
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A Hidden Layer in Your DNA Is Running Your Body
More than 60 years after its discovery, scientists are still learning surprising ways DNA stores and translates instructions for life.
Here’s what you’ll learn when you read this story:
- The genetic building blocks of life—formed from the four nucleotides adenine (A), cytosine (C), guanine (G), and thymine (T)—are read in groups of three known as codons.
- While some codons (known as synonymous codons) code for the same amino acids, recent research shows that these codons behave differently when inside a cell, particularly if mRNA is enriched with non-optimal codons.
- A new study has discovered the underlying mechanism cells use to detect differences between these codons, which could have far-reaching implications for understanding cell differentiation.
When you drill down far enough, life becomes an alphabet soup of letters—four of them to be exact. These nucleotides—adenine (A), cytosine (C), guanine (G), and thymine (T)—form codons that are read in three-letter groups that usually tell cells which amino acid to add to the mix when building a protein. Of the 64 possible combinations of codons, 61 of them code for amino acids, while three (UAA, UAG, UGA) serve as stop signals that represent the end of protein synthesis.
But in some cases, multiple codons actually code for the same amino acid—they’re known as “synonymous codons”—and as you might guess from their name, they were long thought to be interchangeable. However, in recent years, that idea has changed. Scientists have discovered that some synonymous codons are more effective than others at helping messenger RNA (mRNA) remain stable and translate efficiently. For example, if mRNA contains many non-optimal synonymous codons, it translates less efficiently. Scientists didn’t know the hidden mechanism for how cells determine this outcome until now.
In a new study, published in the journal Science, researchers at Kyoto University and RIKEN in Wako, Japan, unveiled this secret layer in human DNA that determines how these differing synonymous codons behave. The researchers used the gene-editing technology CRISPR to scan for gene expression related to codons, and narrowed their finding to a specific RNA-binding protein called DHX29. In follow-up experiments, the research team determined that non-optimal codons accumulated in the absence of DHX29, suggesting that the protein was key to regulating this previously unseen process.
“These findings reveal a direct molecular link between synonymous codon choice and the control of gene expression in human cells,” Masanori Yoshinaga, a co-author of the study from Kyoto University, said in a press statement.
Of course, the question remained: How was the DHX29 protein regulating this process? To find the answer, Yoshinaga and his team turned to cryo-electron microscopy. This technique, also known as cryo-EM, flash-freezes samples and then probes them with electron beams, creating 3D-images of DNA, RNA, proteins, viruses, and cells. It’s an especially effective way to capture how such microscopic structures interact with each other. And in the case of DHX29, it revealed how the protein interacts with 80S ribosomes—the cellular machines responsible for protein synthesis in human cells.
Along with subsequent proteomic analyses, the cryo-EM research revealed that DHX29 binds to ribosomes decoding non-optimal codons and recruits a particular protein complex (with the oh-so-memorable named “GIGYF2•4EHP”) to suppress mRNA filled with these codons. In other words, DHX29identifies sluggish mRNA molecules—those loaded with non-optimal codons—and flags them for disposal.
“We have long been fascinated by how cells interpret the hidden layer of information embedded within the genetic code,” Osamu Takeuchi, senior author of the study from Kyoto University, said in a press statement, “so discovering the molecular factor that allows human cells to read and respond to this hidden code has been particularly rewarding.”
Considering that DHX29 plays a role in cell differentiation and cancer development, revealing this hidden layer of human DNA has profound consequences for understanding these processes. Although the four-nucleotide building blocks of life may seem simple, scientists continue to learn that they’re really anything but.
Darren lives in Portland, has a cat, and writes/edits about sci-fi and how our world works. You can find his previous stuff at Gizmodo and Paste if you look hard enough.