# Post-transcriptional gene regulation by the exon junction complex

> **NIH NIH R35** · OHIO STATE UNIVERSITY · 2024 · $51,076

## Abstract

PROJECT SUMMARY OF THE PARENT PROJECT
The supplement will facilitate the parent grant summarized here by supporting an equipment purchase to fulfill
the original scope of work. Nonsense mutations pose a serious challenge to fitness and survival of cells and
organisms. To suppress mRNAs carrying such nonsense mutations, all eukaryotes possess a conserved mRNA
surveillance pathway called Nonsense-Mediated mRNA Decay (NMD). NMD is also an essential post-
transcriptional regulator of normal mRNAs that shapes processes such as stem cell maintenance, neurogenesis,
germ cell development and anti-viral response. In all eukaryotes, NMD is governed by three UPF proteins, UPF1,
UPF2 and UPF3. In multicellular organisms, NMD is also regulated by a conserved multi-protein exon junction
complex (EJC), which binds upstream of mRNA exon-exon junctions. During translation, if at least one EJC
remains present downstream of a terminating ribosome, it can signal premature termination and trigger NMD.
Understanding NMD mechanism and its regulation by EJC is crucial for betterment of human health as mutations
in EJC and NMD proteins cause developmental defects, intellectual disability and mental retardation. The
overarching goal of this research program is to understand how the remarkable variation in composition and
function of EJC/UPF machinery regulates NMD to dictate cellular function and fate in animal cells. To achieve
this goal, we are using a combination of genetic, genomic, molecular, biochemical and cellular approaches in
cultured human cells and in zebrafish embryos to pursue four main directions. (1) We will identify the mechanism
of a switch in EJC composition that we recently discovered and define the role of distinct EJC compositions in
gene expression. (2) Our recent discovery that mammalian UPF3 paralogs and their interaction with EJC are
non-essential for NMD challenges a decades old model of EJC-dependent NMD in eukaryotes. We will apply
new genomic technologies that probe in vivo ribosome function to identify the role of UPF3 and other UPF
proteins in premature termination complex assembly and activity on hundreds of human mRNAs. We will also
identify the factors and features that govern signaling between the termination complex and the EJC. (3) We and
others have previously shown that EJCs are often detected at unexpected locations on RNAs. By exploiting a
new step in EJC recycling that we have uncovered, we will define the assembly mechanisms and functions of
EJCs at such unexpected sites. (4) We have developed zebrafish mutants that lack one of the EJC or its NMD
adapter proteins, which will be used to identify the genetic and cellular processes controlled by these factors
during motor neuron and muscle development. Overall, our work will advance the knowledge of NMD
mechanisms and how they regulate post-transcriptional gene regulation to control cellular function and
organismal development. This progress will also elevate our ability to target ...

## Key facts

- **NIH application ID:** 11100080
- **Project number:** 3R35GM149298-02S1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Guramrit Singh
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $51,076
- **Award type:** 3
- **Project period:** 2024-08-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100080

## Citation

> US National Institutes of Health, RePORTER application 11100080, Post-transcriptional gene regulation by the exon junction complex (3R35GM149298-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11100080. Licensed CC0.

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