Grant: Discovery Grants Program - Individual

One of the most fundamental activities in living systems is to copy their genetic information (DNA) into proteins, the molecular machines that carry out most of the biological functions that keep an organism alive. The copying of DNA into proteins occurs in two steps: first, DNA is copied into mRNA (messenger ribonucleic acid; chemically similar to DNA); second, mRNA is used as a template to make specific proteins. The amount of proteins is therefore dependent on the amount of mRNAs. An excess or shortage of many proteins due to changes in the abundance of mRNA can lead to diseases, such as cancer. The abundance of mRNAs is highly dependent on the rate of its degradation. An understanding of how the mRNA degradation machinery works is therefore important for increasing our basic scientific knowledge of molecular biology, as well as for revealing information on the pathogenesis of some human diseases. It has been widely believed that mammalian mRNAs are primarily degraded from the ends of the molecules. However several recent reports including a publication from our own laboratory are beginning to challenge this view. These report have shown that mRNAs can also be degraded through cleavage in the middle of the molecules - a process known as endonucleolytic cleavage. Enzymes that initiate endonucleolytic cleavage are called endoribonucleases. Our laboratory has recently identified APE1 as an endoribonuclease that cleaves c-myc mRNA in a test tube. We have also shown that APE1 can influence the abundance and longevity of c-myc mRNA in cells. The goals of our proposed research are to determine the RNA targets of APE1 in cells, and to ascertain whether it is an important endoribonuclease for controlling the abundance of various RNA molecules. Results generated from these studies have high potential to advance our knowledge of gene expression, as well as possibly leading to the use of the enzyme or its properties in RNA degradation technology.