"Non-technical" abstract

Understanding the Control of mRNA-Protein Interactions During Stress and Disease

Figure 1: An overview of gene expression and the mRNA life cycle

Gene expression describes how the genetic information in DNA produces the proteins that perform most of the work in cells (see Figure 1 for the basic steps involved). Alterations in gene expression are crucial in many diseases such as cancer, viral infection, developmental disorders, aging, and others. The instructions for producing a protein are carried from the DNA to the protein synthesis machinery by a molecule called messenger RNA (mRNA). The Bolger lab focuses on understanding how cells turn the information in the mRNA into a protein, a process called protein translation.

A family of enzymes, called DEAD-box proteins (DBPs), are involved in many steps of gene expression and are critical for regulating mRNAs appropriately. A DBP called Ded1 plays several important roles in protein translation, making sure that the right proteins are made at the right time. Alterations in the human version of Ded1, called DDX3X, have been linked to several diseases, including: cancer, especially the brain cancer medulloblastoma; a developmental disorder in children; and infection by several viruses, including hepatitis and HIV.

Current research in the Bolger lab seeks to understand how translation is controlled through enzymes like Ded1/DDX3X. A major aim is to understand translational control during cell stress conditions, such as when cells lack nutrients or are exposed to extreme temperatures. This project is being performed using yeast cells, which allows us to take advantage of techniques that are difficult or impossible in human cells. The gene expression machinery is highly similar in yeast and humans, so discoveries made in yeast should be directly applicable to human biology. Loss of the ability to mount a proper response to stress is associated with both cancer progression and as a result of aging. Our work may therefore be helpful in combatting these diseases. 

Likewise, a second aim is to understand how DDX3X contributes to the development of medulloblastoma. For this work we are using both yeast and mammalian cells, leveraging the advantages of each model system. In the future, this work may lead to improved chemotherapies for medulloblastoma that cause fewer long-term issues in patients.