Grant: Discovery Grants Program - Individual

Genetic information is stored in the form of DNA found in a cell compartment called the nucleus.  This genetic information has to be transported out of the nucleus into the extra-nuclear cytoplasm where gene products or proteins are made.  Messenger ribonucleic acids or mRNAs are the bio-molecules that carry the genetic information from DNA in the nucleus to the cytoplasm.  mRNAs which carry the genetic code for each gene are then used for the synthesis of proteins.  The proteins then carry out most of the important biochemical functions of the cells.  The amount of proteins is directly dependent on the amount of mRNAs.  Excessive or insufficient amounts of certain proteins due to changes in mRNA levels can lead to diseases.  The amount of mRNA is in large part determined by the rate of its degradation.  An understanding of how mRNA is degraded is therefore important for generating basic knowledge of how mRNA degradation machinery works, as well as for revealing information on the pathogenesis of some diseases.  It is widely believed that mRNAs from eukaryotes, including mammals, are degraded primarily from ends of the molecule.  mRNA is also known to be degraded via cleavage in the middle of the molecule - a process known as endonucleolytic cleavage.  However, little is known about the enzymes (endonucleases) that cleave mammalian mRNAs endonucleolytically and what role they play in controlling mRNA abundance in cells.  Our laboratory has recently purified, characterized, and identified at least two mammalian endonucleases, syntaxin18 and RNase1, that can cleave c-myc mRNA in test tubes.  Syntaxin18 is involved in the mechanism of protein movement in cells but it has not been previously described as an endonuclease.  The major goal of our research is to determine whether syntaxin18 and RNase1 can control mRNA abundance in cells.  This will help us in understanding the significance of endonucleolytic cleavage in controlling mRNA abundance.  In addition, such knowledge has the potential in leading to the use of these enzymes or their properties in applied research.