Animal replication-dependent histone mRNAs are the only eukaryotic mRNAs that lack a polyA tail ending instead in a conserved stemloop. In contrast mRNAs for histone variants, e.g. H3.3 and H2a.z, are encoded by polyadenylated mRNAs. The genes for all five histone proteins are clustered in metazoan genomes, and factors required for histone gene expression are concentrated near the histone genes. Our goal is to understand the detailed mechanisms unique to histone mRNA metabolism and regulation, which occurs primarily at the posttranscriptional level, both regulating histone pre-mRNA processing and histone mRNA degradation. The stemloop is the major cis element responsible for both these regulatory steps. cell cycle regulation of histone mRNAs. The three aims of this proposal are: 1. Understand how the histone pre-mRNA is cleaved by a set of factors also used in cleavage and polyadenylation, which specifically assemble on the U7 snRNP and cleave the histone pre- mRNA. 2. Understand the biochemical details, including the mechanism of regulation, of the novel pathway of histone mRNA degradation which is initiated by oligouridylation of the histone mRNA, and requires the RNA helicase Upf1 as well as at least two 3' to 5' exonucleases and terminal uridyl transferases. 3. Understand how the factors required for histone mRNA biosynthesis interact in the histone locus body (HLB), and whether the assembly of the U7 snRNP is regulated by structural changes in the HLB.
We study the regulation of the synthesis of histone proteins, which package the DNA into the chromosome; each time DNA is replicated, histones must be synthesized in large amounts to package the newly replicated DNA into chromosomes. Histone mRNAs differ in structure from all other mRNAs in the cell, and there are a dedicated set of factors and pathways required for histone mRNA metabolism and regulation. We have elucidated many of these pathways, and will define in detail how these factors function and their activity is regulated to ensure the proper transfer of genetic information each time a cell divides
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