The replication dependent histone mRNAs are the only metazoan mRNAs that are not polyadenylated. Instead they end in a conserved stemloop structure. The synthesis of histone proteins is tightly coupled to DNA replication and this is controlled largely by regulating histone mRNA. In early embryos, all organisms must produce histone proteins in the absence of transcription, and many embryos, including frogs and Drosophila, must produce massive amounts of histone proteins in a short time during the extremely rapid early cell divisions. We have carried out a genome wide RNAi screen for factors involved in histone mRNA processing using Drosophila cultured cells. We will determine the function of these factors in the processing reaction (components of the U7 snRNP and the cleavage factor) as well as other possible previously unknown factors, and identify which factors are present in the Histone Locus Body. We also obtained factors involved in replication-independent chromatin assembly in the screen suggesting that the pathways for replication-dependent and replication-independent histone protein metabolism directly interact. We will determine the role of these factors in histone mRNA regulation in the fly, using available mutants in many of these factors. We will also determine the molecular mechanism of regulation of histone mRNA translation in Xenopus oocytes, focusing on the role of the stemloop binding protein, and a novel protein that it interacts with, in translation. This novel protein, SLIP1, is likely involved in translation regulation of other mRNAs, and we will identify what other pathways it participates in.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058921-11
Application #
7727383
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Bender, Michael T
Project Start
1999-05-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
11
Fiscal Year
2010
Total Cost
$367,270
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
608195277
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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