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.

Public Health Relevance

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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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 428:1180-96
Borchardt, Erin K; Vandoros, Leonidas A; Huang, Michael et al. (2015) Controlling mRNA stability and translation with the CRISPR endoribonuclease Csy4. RNA 21:1921-30
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
Brooks 3rd, Lionel; Lyons, Shawn M; Mahoney, J Matthew et al. (2015) A multiprotein occupancy map of the mRNP on the 3' end of histone mRNAs. RNA 21:1943-65
Yang, Xiao-cui; Sabath, Ivan; Kunduru, Lalitha et al. (2014) A conserved interaction that is essential for the biogenesis of histone locus bodies. J Biol Chem 289:33767-82
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
Djakbarova, Umidahan; Marzluff, William F; Koseoglu, M Murat (2014) Translation regulation and proteasome mediated degradation cooperate to keep stem-loop binding protein low in G1-phase. J Cell Biochem 115:523-30
Lyons, Shawn M; Ricciardi, Adele S; Guo, Andrew Y et al. (2014) The C-terminal extension of Lsm4 interacts directly with the 3' end of the histone mRNP and is required for efficient histone mRNA degradation. RNA 20:88-102
Slevin, Michael K; Meaux, Stacie; Welch, Joshua D et al. (2014) Deep sequencing shows multiple oligouridylations are required for 3' to 5' degradation of histone mRNAs on polyribosomes. Mol Cell 53:1020-30

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