Regulation of Gene Processing in Disease

Ambro van Hoof, Ph.D., assistant professor, microbiology and molecular genetics,
Medical School and GSBS

Ambro van Hoof, Ph.D.

You have a check that signifies money is owed to you. To turn it into cash, you go to a bank or ATM, which acts to “translate” your check into hard cash.

Similarly, DNA is a message that must be translated to mean something to the cell.

Within the nucleus of a cell lies DNA – the genetic material that defines how your body works. The DNA message needs to be delivered to the cytoplasm (the substance between the nucleus and the membrane wall) of the cell to tell assembling elements there to make a functional protein for which that gene codes. Messenger RNA (mRNA) is the “check” sent to accomplish this task.

“Gene expression is a complex process that all life forms need to carry out in a precisely controlled fashion,” said Ambro van Hoof, Ph.D. Dysregulation of this process can cause different diseases, depending upon the genes affected. Van Hoof studies one way in which this process may go awry – degradation of mRNA after it has sent its message.

“The degradation of mRNA is one of the last steps in gene expression and serves important roles in this process,” van Hoof said. Disruption of this process may result in abnormal protein levels or affect the processing of other gene products.

mRNA that is translated into protein has a stop signal to tell the cellular machinery that the job of translation is finished. mRNA lacking this stop signal is called “nonstop” mRNA.

“We concentrate on these mRNAs because they are extremely rapidly degraded, but they are degraded by the same enzymes that degrade other mRNAs,” van Hoof said. “We hope that if we understand nonstop mRNA decay in detail, this will also help us understand how normal mRNAs are degraded.”

Although van Hoof’s studies are performed in a yeast model system, discovering how mRNA decay is regulated has wide benefits. “Nonstop mRNAs are also made in human cells, and nonstop mRNA decay may contribute to human disease,” he said.

For example, “in most humans there is only one stop signal in the APRT (adenine phosphoribosyltransferase) gene. In patients where this stop signal is mutated to any other signal, the APRT mRNA is very rapidly degraded, and less APRT protein is made,” he explained. Since this protein is particularly important to kidney function, a reduced amount of this protein is related to kidney disease.

Another example of the human applicability of nonstop RNA is the GPR54 (G protein-coupled receptor 54) gene. “If the only stop signal in this gene is mutated, the mRNA is rapidly degraded, and the encoded protein is not made. As a result, these patients fail to develop normally during puberty and are sterile,” van Hoof said.

By facilitating the understanding of the complex mechanism by which genes are regulated, research on nonstop mRNAs applies to a wide array of diseases with defects in mRNA decay.