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)
Type
Research Project (R01)
Project #
5R01GM058921-15
Application #
8703715
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
Project End
Budget Start
Budget End
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
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
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
Terzo, Esteban A; Lyons, Shawn M; Poulton, John S et al. (2015) Distinct self-interaction domains promote Multi Sex Combs accumulation in and formation of the Drosophila histone locus body. Mol Biol Cell 26:1559-74
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
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
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
Tatomer, Deirdre C; Rizzardi, Lindsay F; Curry, Kaitlin P et al. (2014) Drosophila Symplekin localizes dynamically to the histone locus body and tricellular junctions. Nucleus 5:613-25
Marzluff, William F; Duronio, Robert J (2014) Genome stress response in early development. Dev Cell 29:375-6
Zhang, Jun; Tan, Dazhi; DeRose, Eugene F et al. (2014) Molecular mechanisms for the regulation of histone mRNA stem-loop-binding protein by phosphorylation. Proc Natl Acad Sci U S A 111:E2937-46
Dominski, Zbigniew; Carpousis, Agamemnon J; Clouet-d'Orval, Béatrice (2013) Emergence of the β-CASP ribonucleases: highly conserved and ubiquitous metallo-enzymes involved in messenger RNA maturation and degradation. Biochim Biophys Acta 1829:532-51

Showing the most recent 10 out of 46 publications