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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029832-38
Application #
8478120
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
1982-07-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
38
Fiscal Year
2013
Total Cost
$376,826
Indirect Cost
$121,485
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
Borchardt, Erin K; Meganck, Rita M; Vincent, Heather A et al. (2017) Inducing circular RNA formation using the CRISPR endoribonuclease Csy4. RNA 23:619-627
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
Marzluff, William F; Koreski, Kaitlin P (2017) Birth and Death of Histone mRNAs. Trends Genet 33:745-759
Aik, Wei Shen; Lin, Min-Han; Tan, Dazhi et al. (2017) The N-terminal domains of FLASH and Lsm11 form a 2:1 heterotrimer for histone pre-mRNA 3'-end processing. PLoS One 12:e0186034
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
Lyons, Shawn M; Cunningham, Clark H; Welch, Joshua D et al. (2016) A subset of replication-dependent histone mRNAs are expressed as polyadenylated RNAs in terminally differentiated tissues. Nucleic Acids Res 44:9190-9205
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

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