Histone mRNA levels are tightly coordinated with DNA replication to ensure proper replication of chromatin. The replication-dependent histone genes encode the only non-polyadenylated mRNAs is eukaryotic cells. These mRNAs end in a conserved stemloop, which interacts with the stemloop binding protein, SLBP. The stem-loop/SLBP complex functions in all steps of histone mRNA metabolism in place of the polyA tail. Most of the regulation of histone mRNA levels is posttranscriptional and is mediated by the stemloop/SLBP complex. Formation of the 3'end of histone mRNA is cell-cycle regulated, primarily mediated by controlling the levels of SLBP. We will determine the additional components that recruit the cleavage factor to the histone pre-mRNA pre-processing complex. There are likely factors that regulate processing that influence this recruitment and we will characterize both positive and negative factors, involved in this critical regulatory step. The second regulatory step that coordinates histone mRNA levels with DNA replication is regulation of histone mRNA half-life. Histone mRNA degradation is initiated by oligouridylation of the 3'end. We will identify the terminal uridyl transferase (TUTase) involved in the oligouridylation, and the mechanism by which the TUTase is recruited to activate histone mRNA degradation. These studies will allow us to identify novel factors and modifications involved in coupling DNA replication with histone mRNA degradation.
Each S-phase the cell must properly replicate its genome, and package the newly replicated DNA into chromatin. The levels of histone mRNA are tightly controlled by regulating both 3'end formation and mRNA degradation. We will determine the biochemical mechanisms that couple histone mRNA metabolism with DNA replication.
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