Regulating Human Translation

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Human bodies are quite complex, with many different cell types and tissues, but only one genome. To put information in our genome into action, the different steps of gene expression must be regulated to lay out our body plan, and to maintain it. We are beginning to appreciate that regulating when and where proteins are made from the messenger RNA (mRNA) copies of our genes is critical for us to develop and stay healthy.

Proteins are polymers, which means protein synthesis–or translation–happens in three overall steps: initiation, elongation, and termination. In all of life, translation initiation is heavily regulated. That's probably because it's better not to start making a protein until it's needed, rather than stopping in the middle of making it. In humans, translation initiation involves many general translation factors, proteins and protein complexes called eukaryotic translation initiation factors or eIFs. We have focused on eIF3, because its large size remains a mystery.

Human eIF3 is targeted by viruses like the hepatitis C virus that highjack translation for their own ends. We think that these viruses are tapping in to specific ways that eIF3 is used in normal human biology. With this idea in mind, we recently discovered that eIF3 is more than a general translation initiation factor. It can activate or repress translation of specific mRNAs that control how cells grow and divide. Notably, a number of these mRNAs encode key proteins involved in cancer. We're now working to understand how eIF3 binds these mRNAs to turn them on or off. We know that RNA structure is likely involved, rather than just a linear sequence pattern. We're also interested to find out if eIF3 regulates other mRNAs in different kinds of cells. To answer these questions, we are using systems biology, biochemistry and structural biology.

 
 

The Voracious Yeast Project

We use the yeast Saccharomyces cerevisiae to make bread and beer and biofuels, but this yeast has a rather picky diet. It prefers sugars that are easy to ferment, such as sucrose and glucose. Although it will consume other sources of carbon, these sources slow S. cerevisiae down. This forces us to use food crops such as corn and sugarcane to make renewable fuels and chemicals.

Perennial plants such as grasses and fast-growing trees fix carbon in the plant cell wall, a carbon source that could be used to make biofuels to substitute for gasoline, diesel, and jet fuels, and to make renewable chemicals. But plants are made of sugars that our favorite industrial yeast S. cerevisiae doesn’t like, or doesn’t consume at all. Other fungi, such as Neurospora crassa, are not so selective and actually make a living by consuming these sugars in burnt grasslands.

We found that N. crassa consumes sugars in the plant cell wall as short soluble chains, quite a different strategy compared to S. cerevisiae or other yeasts. We think that engineering yeast to consume sugars from plants the way N. crassa does will open many new ways to use S. cerevisiae to make biofuels and chemicals for a green economy. We have the parts (pathways) from N. crassa mostly worked out. But to make them work in S. cerevisiae–to make a Voracious Yeast–will take cutting-edge systems biology and synthetic biology.

 

Translation Elongation

We are also interested in how cells make proteins that reside in membranes or are secreted. Finally, we are thinking about ways to engineer bacterial ribosomes to make new kinds of polymers, rather than proteins. These projects are in their early stages of development. Stay tuned for updates!