# Translational Control by Human Pumilio Proteins

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $379,675

## Abstract

Project Summary
 The human RNA-binding proteins, PUM1 and PUM2, are essential for mammalian development and their
dysfunction is linked to multiple human diseases including developmental defects, neurological disorders,
infertility, cancers, and mitochondrial dysfunction. These important functions compel our overall objective to
discover how PUM1&2 control the flow of genetic information from gene to mRNA to protein and to identify the
full repertoire of genes that they regulate. PUM1&2 bind to thousands of mRNAs in human cells by recognizing
an RNA sequence called the Pumilio Response Element (PRE). Previous research showed that PUM1&2
promote degradation of hundreds of these PRE-containing mRNAs by recruiting RNA decay enzymes. It is now
clear, however, that this mechanism represents only one type of PUM-mediated regulatory outcome. Thousands
of mRNAs are bound by PUM1&2 but are not degraded. Therefore, it is now necessary to determine how
PUM1&2 control the fate of all target mRNAs. The resulting data will provide a comprehensive view of their
regulatory roles in biology and pathogenesis.
 We propose that human PUM1&2 repress many target mRNAs by inhibiting the process of translation.
This hypothesis is supported by multiple examples of genes that are repressed by PUM1&2 at the level of protein
abundance in the absence of mRNA degradation. The mechanism and prevalence of this translational inhibition
is unknown. In addition, our data indicate that for some genes PUM-mediated translational inhibition can
synergize with RNA degradation to regulate gene expression to a larger extent than either process alone.
 RNA molecules form structures that influence their function and fate. While biochemical evidence
indicates that RNA structure can modulate PUM-PRE interactions, its effect in vivo remains unknown. In fact,
there is an overall lack of RNA structural information of mRNAs in human cells that limits our understanding of
how that structure influences gene regulation by RNA-binding proteins like PUM1&2.
 The proposed research seeks to determine how PUM1&2 inhibit translation and to identify the
translational regulatory factors that are necessary for PUM1&2 activity. The structure of human mRNAs will be
determined and its effect on PUM-mRNA interactions and regulatory network will be analyzed. By integrating
this new data with existing knowledge of which mRNAs are bound and degraded by PUM1&2, we will develop a
comprehensive understanding of this key genetic regulatory network. Discovery of the full regulatory network of
PUM1&2 will provide new insights into how they control gene expression to regulate normal biological processes.
Moreover, this knowledge will help elucidate how their dysfunction leads to diseases such as neurodegeneration
and cancer.

## Key facts

- **NIH application ID:** 10909895
- **Project number:** 5R01GM150468-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Aaron Charles Goldstrohm
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $379,675
- **Award type:** 5
- **Project period:** 2023-08-18 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909895

## Citation

> US National Institutes of Health, RePORTER application 10909895, Translational Control by Human Pumilio Proteins (5R01GM150468-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909895. Licensed CC0.

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