Histone mRNA levels are tightly coordinated with DNA replication to ensure proper replication of chromatin. The replication-dependent histone genes encode the only non-polyadenylated mRNAs is eukaryotic cells. These mRNAs end in a conserved stemloop, which interacts with the stemloop binding protein, SLBP. The stem-loop/SLBP complex functions in all steps of histone mRNA metabolism in place of the polyA tail. Most of the regulation of histone mRNA levels is posttranscriptional and is mediated by the stemloop/SLBP complex. Formation of the 3'end of histone mRNA is cell-cycle regulated, primarily mediated by controlling the levels of SLBP. We will determine the additional components that recruit the cleavage factor to the histone pre-mRNA pre-processing complex. There are likely factors that regulate processing that influence this recruitment and we will characterize both positive and negative factors, involved in this critical regulatory step. The second regulatory step that coordinates histone mRNA levels with DNA replication is regulation of histone mRNA half-life. Histone mRNA degradation is initiated by oligouridylation of the 3'end. We will identify the terminal uridyl transferase (TUTase) involved in the oligouridylation, and the mechanism by which the TUTase is recruited to activate histone mRNA degradation. These studies will allow us to identify novel factors and modifications involved in coupling DNA replication with histone mRNA degradation.

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PROJECT NARRATIVE Each S-phase the cell must properly replicate its genome, and package the newly replicated DNA into chromatin. The levels of histone mRNA are tightly controlled by regulating both 3'end formation and mRNA degradation. We will determine the biochemical mechanisms that couple histone mRNA metabolism with DNA replication.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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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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Skrajna, Aleksandra; Yang, Xiao-Cui; Dadlez, Michal et al. (2018) Protein composition of catalytically active U7-dependent processing complexes assembled on histone pre-mRNA containing biotin and a photo-cleavable linker. Nucleic Acids Res 46:4752-4770
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
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Lackey, Patrick E; Welch, Joshua D; Marzluff, William F (2016) TUT7 catalyzes the uridylation of the 3' end for rapid degradation of histone mRNA. RNA 22:1673-1688
Skrajna, Aleksandra; Yang, Xiao-Cui; Tarnowski, Krzysztof et al. (2016) Mapping the Interaction Network of Key Proteins Involved in Histone mRNA Generation: A Hydrogen/Deuterium Exchange Study. J Mol Biol 428:1180-1196
Djakbarova, Umidahan; Marzluff, William F; Köseo?lu, M Murat (2016) DDB1 and CUL4 associated factor 11 (DCAF11) mediates degradation of Stem-loop binding protein at the end of S phase. Cell Cycle 15:1986-96
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