Pathway of histone mRNA degradation: oligouridylation followed by bidirectional decay Public Deposited

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  • March 22, 2019
  • Mullen, Thomas Edward, Jr.
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
  • Histone mRNAs are rapidly degraded at the end of S phase or when DNA replication is inhibited. Histone mRNAs end in a conserved stemloop rather than a poly(A) tail. Degradation of histone mRNAs requires the stemloop sequence, which binds the stemloop binding protein (SLBP), active translation of the histone mRNA, and the location of the stemloop close to the termination codon. In this thesis I present evidence that the initial step in histone mRNA degradation is the addition of uridines to the 3' end of the histone mRNA, both after inhibition of DNA replication and at the end of S-phase. Lsm1 is required for histone mRNA degradation and is present in a complex containing SLBP on the 3' end of histone mRNA after inhibition of DNA replication. I cloned degradation intermediates that had been partially degraded from both the 5' and the 3' end. RNA interference (RNAi) experiments demonstrate that both the exosome (3'-5') and 5' to 3' decay pathway components are functionally required for degradation. cRT-PCR experiments corroborate the findings from the functional RNAi experiments by providing direct evidence that individual histone mRNAs are degraded simultaneously 5' to 3' and 3' to 5' when DNA synthesis is inhibited. Finally, I present evidence that SLBP protein expression is required for proper regulation of histone mRNA degradation when DNA synthesis is inhibited, but that the underlying mechanism is due to nuclear retention of properly processed histone mRNA. The latter suggests that one of the critical functions of SLBP in human cells is the proper export of histone mRNA to the cytoplasm.
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  • Marzluff, William
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  • University of North Carolina at Chapel Hill
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