# Control of Histone mRNA Levels

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $449,174

## Abstract

ABSTRACT
 Animal replication-dependent histone mRNAs are the only eukaryotic mRNAs that lack a
polyA tail ending instead in a conserved stemloop. In contrast mRNAs for histone variants, e.g.
H3.3 and H2A.Z, are encoded by polyadenylated mRNAs. The genes for all five histone
proteins are clustered in metazoan genomes, and factors required for histone gene expression
are concentrated near the histone genes. A nuclear body, the histone locus body (HLB) forms
at the histone genes and contains factors essential for histone mRNA biosynthesis. Our goal is
to understand the detailed mechanisms unique to histone mRNA metabolism and regulation,
which occurs primarily at the posttranscriptional level, both regulating histone pre-mRNA
processing and histone mRNA degradation. The stemloop is the major cis element responsible
for both these regulatory steps in the cell cycle regulation of histone mRNAs. The three aims of
this proposal are: 1. Using an in vitro processing system composed primarily of recombinant
proteins and synthetic RNAs to understand how the histone pre-mRNA is cleaved by a set of
factors also used in cleavage and polyadenylation. These factors specifically assemble on the
U7 snRNP. In particular we will determine the specific interactions between the U7 snRNP, the
substrate and SLBP which activate the endonuclease CPSF73 for cleavage. 2. Understand the
biochemical details, including the mechanism of regulation, of the novel pathway of histone
mRNA degradation. Using CRISPR-Cas9 to edit the factors required for degradation, we will
determine the mechanism by which the uridyl transferase TUT7 is recruited to modify histone
mRNA, and the role of Upf1 in this process. 3. Understand how histone mRNA expression is
regulated by factors present in the HLB, focusing on the changes that occur as cells progress
from G1 to S-phase. NPAT, the major scaffolding factor, and FLASH, the factor required for
assembly of the active U7 snRNP, are large, largely unstructured proteins, that contain small
domains that interact with specific factors. We are characterizing the factors that interact with
these proteins to determine factors involved in coordinate regulation of histone gene expression.

## Key facts

- **NIH application ID:** 9989884
- **Project number:** 5R01GM029832-45
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** ZBIGNIEW DOMINSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $449,174
- **Award type:** 5
- **Project period:** 1982-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989884

## Citation

> US National Institutes of Health, RePORTER application 9989884, Control of Histone mRNA Levels (5R01GM029832-45). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9989884. Licensed CC0.

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