CAREER: The Role of Drosophila SLBP in Histone Gene Expression and Cell Cycle Progression

University Of North Carolina At Chapel Hill, Chapel Hill NC

Investigators

Abstract

One of the most fundamental aspects of eukaryotic cell biology is the control of the cell division cycle. The canonical eukaryotic cell division cycle is usually described as having four phases that occur in a precise order: G1-S-G2-M. Most cells typically make a decision whether or not to enter into a new cell cycle during G1 phase. Cyclins, members of a family of serine/threonine protein kinases consisting of a catalytic subunit (cdk) bound to a regulatory subunit, have been shown to be the principle regulators of the cell cycle. Cyclin/cdk-mediated phosphorylation of key target molecules during G1 is thought to trigger a series of downstream events leading to the initiation of DNA replication and cell cycle progression. However, nothing is known about the mechanisms involved. Histone genes are a unique class of genes that encode the only mRNAs that lack poly-adenylated tails. They are synthesized and accumulated in the S phase prior to DNA replication although the mechanisms that couple histone synthesis to other events in the cell cycle are largely unknown. Most of the cell cycle regulation of histone mRNA is post-transcriptional and mediated by the 3' end of histone mRNA, which contains a conserved 26 nucleotide sequence that forms a stem-loop. cDNAs encoding a protein that binds the 3'end of histone mRNA (called the stem-loop binding protein or SLBP) has recently been identified from a variety of animal species. SLBP is a novel RNA binding protein that is thought to participate in all aspects of histone mRNA metabolism. Moreover, SLBP may provide the molecular link between cell cycle progression and histone biosynthesis. To test these hypotheses using genetic tools, SLBP will be studied in Drosophila melanogaster. The specific aims are:1)To characterize dSLBP and histone mRNA accumulation during development 2) To analyze and characterize the phenotype of the dSLBP mutants 3) To study the regulation of dSLBP during the cell cycle and development. Working with undergraduate students as well as graduate students both in the laboratory and in the classroom will be a significant aspect of this project. Although students often express a desire to enter the battle against human diseases such as cancer, they have little understanding of the importance of model systems in the quest for an understanding of the underlying mechanisms causing the disease. A course will be developed with a specific emphasis on the importance of the genetics of invertebrate experimental systems like Drosophila, C. elegans, and yeast in shedding light on the function of genes known to play a role in human disease.