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 H2.v, 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 localized near the histone genes. We will determine the requirements for the coordinate expression of the replication-dependent histone mRNAs in vivo using Drosophila as a model system, and in particular the role of the Histone Locus Body in histone mRNA metabolism. We will use both biochemical and genetic approaches to determine 1. The structural requirements in the HLB components FLASH and NPAT required for efficient production of properly processed histone mRNA, 2. The sequences in the histone gene locus that specifies the formation of the HLB at the histone locus and 3. The composition of the histone cleavage factor, which contains polyadenylation factors Symplekin, CPSF73 and CPSF100, will be determined and the role of Symplekin in histone pre-mRNA processing in vitro and in vivo elucidated.

Public Health Relevance

We will combine biochemical and genetic studies in the fruit fly to study the regulation of the synthesis of histone proteins, which are complexed with the DNA chromosome. Each time DNA is replicated, histones are synthesized in large amounts to package the new DNA into chromosomes. Factors controlling histone synthesis are critical for stable inheritance of genetic information and proper development of the organism;these factors are conserved between humans and flies and our genetic studies in flies will allow us to understand their function in humans.

National Institute of Health (NIH)
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Molecular Genetics B Study Section (MGB)
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Bender, Michael T
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Marzluff, William F; Duronio, Robert J (2014) Genome stress response in early development. Dev Cell 29:375-6
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Dominski, Zbigniew; Carpousis, Agamemnon J; Clouet-d'Orval, BĂ©atrice (2013) Emergence of the ?-CASP ribonucleases: highly conserved and ubiquitous metallo-enzymes involved in messenger RNA maturation and degradation. Biochim Biophys Acta 1829:532-51
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Yang, Xiao-Cui; Burch, Brandon D; Yan, Yan et al. (2009) FLASH, a proapoptotic protein involved in activation of caspase-8, is essential for 3'end processing of histone pre-mRNAs. Mol Cell 36:267-78
Kennedy, Sarah A; Frazier, Monica L; Steiniger, Mindy et al. (2009) Crystal structure of the HEAT domain from the Pre-mRNA processing factor Symplekin. J Mol Biol 392:115-28

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