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Project II
The Role of SLBP in Replication Associated Histone mRNA Expression

Many events occur downstream of E2F activation as cells proceed into S phase. One of these events is histone biosynthesis. This project involves an analysis of replication associated histone expression occurs during Drosophila development, and how this is coupled to the cell cycle.
Histone mRNA biosynthesis
Replication associated histone genes encode a class of mRNAs that are tightly regulated during the cell cycle, being expressed only during S phase. Metazoan replication associated histone mRNAs are not polyadenylated, but instead end in a conserved 26 nucleotide sequence that contains a 16 nucleotide stem-loop, with a six base-pair stem and a 4 nucleotide loop (see Figure). Histone genes lack introns, and the only processing step necessary to synthesize a mature mRNA is an endonucleolytic cleavage forming the 3' end and probably releasing the transcript from the chromatin template. Two cis elements are required for processing, the stem loop at the 3' end of the mRNA and a purine-rich sequence about 10 nucleotides from the 3' end that base pairs with the 5' end of U7 snRNA. There are two known trans-acting factors involved in histone mRNA metabolism, a protein that binds the 3' end of histone mRNA (SLBP-see below). The regulation of histone mRNA synthesis is largely post-transcriptional and is mediated by the 3' end of the histone mRNA.

The role of SLBP in histone mRNA metabolism
The 3' untranslated region (UTR) has important roles in the metabolism and regulation of many mature mRNAs. Sequences in the 3' UTR are involved in proper subcellular localization of mRNAs, in the translation of the mRNA and are usually the critical elements which determine the half-life of the mRNA. Two components of the 3' UTR, sequence specific elements 5' of the poly A tail and the poly A tail itself, mediate these effects. For histone genes, mRNA metabolism is mediated by the 3' stem loop, which is required for processing, transport, and translation. Our collaborator in this project, Bill Marzluff, and others have cloned a gene encoding a novel RNA binding protein termed "stem-loop binding protein" (SLBP), which binds the 3' end of histone mRNA. Our central hypothesis is that all aspects of histone mRNA metabolism require SLBP, and we are testing this genetically in Drosophila. In addition, our research direction will emphasize how SLBP might coordinate histone mRNA expression with the cell cycle. If you would like more detail of this project, click here.