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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058921-15
Application #
8703715
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
1999-05-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Rieder, Leila E; Koreski, Kaitlin P; Boltz, Kara A et al. (2017) Histone locus regulation by the Drosophila dosage compensation adaptor protein CLAMP. Genes Dev 31:1494-1508
Duronio, Robert J; Marzluff, William F (2017) Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body. RNA Biol 14:726-738
Skrajna, Aleksandra; Yang, Xiao-Cui; Bucholc, Katarzyna et al. (2017) U7 snRNP is recruited to histone pre-mRNA in a FLASH-dependent manner by two separate regions of the stem-loop binding protein. RNA 23:938-951
Meserve, Joy H; Duronio, Robert J (2017) A population of G2-arrested cells are selected as sensory organ precursors for the interommatidial bristles of the Drosophila eye. Dev Biol 430:374-384
Marzluff, William F; Koreski, Kaitlin P (2017) Birth and Death of Histone mRNAs. Trends Genet 33:745-759
Tatomer, Deirdre C; Terzo, Esteban; Curry, Kaitlin P et al. (2016) Concentrating pre-mRNA processing factors in the histone locus body facilitates efficient histone mRNA biogenesis. J Cell Biol 213:557-70
Swanson, Christina I; Meserve, Joy H; McCarter, Patrick C et al. (2015) Expression of an S phase-stabilized version of the CDK inhibitor Dacapo can alter endoreplication. Development 142:4288-98
Welch, Joshua D; Slevin, Michael K; Tatomer, Deirdre C et al. (2015) EnD-Seq and AppEnD: sequencing 3' ends to identify nontemplated tails and degradation intermediates. RNA 21:1375-89
Meserve, Joy H; Duronio, Robert J (2015) Scalloped and Yorkie are required for cell cycle re-entry of quiescent cells after tissue damage. Development 142:2740-51
McKay, Daniel J; Klusza, Stephen; Penke, Taylor J R et al. (2015) Interrogating the function of metazoan histones using engineered gene clusters. Dev Cell 32:373-86

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