# Nonsense-mediated mRNA Decay and Nonsense-Mediated mRNA Decay Factors

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $30,228

## Abstract

This R01 extends our studies of nonsense-mediated mRNA decay (NMD) and its constituent factors and
effectors in human and mouse cells and, since the last competitive renewal, using mice. NMD controls the
quality of gene expression by preventing the production of potentially toxic proteins in health and in disease.
It provides for the autoregulation of many RNA-binding proteins that regulate the splicing of the pre-mRNA
from which they derive. NMD also promotes the adaptation of cells to changing environments utilizing the
~10% of cellular mRNAs that are natural NMD targets. Aim 1 proposes to pursue our exciting finding that
the abundance of NMD factors and the efficiency of NMD are upregulated in human neuronal cells deficient
in Fragile X Mental Retardation Protein (FMRP). FMRP deficiency typifies Fragile X Syndrome (FXS), which
is the most common single-gene cause of intellectual disability and autism. We will analyze the mechanistic
and metabolic defects that typify the neuronal differentiation pathway of (i) SH-SY5Y neuroblastoma cells in
which we have knocked-out the FMRP-encoding gene, FMR1, using CRISPR-Cas9n technology, and (ii)
induced pluripotent stem cells (iPSCs) that we have generated from FXS-patient fibroblasts. Aim 2
proposes to characterize the functional significance of our finding that cap-binding protein 80 (CBP80)
directly binds the transcriptional co-activator PGC-1α. CBP80 is one subunit of the cap-binding heterodimer
that is acquired co-transcriptionally during the expression of protein-encoding genes and, we have shown,
persists through the pioneer round of translation, during which it functions in NMD. PGC-1α promotes
mitochondrial energy-generating functions in response to physiological stresses that become
bioenergetically sub-optimal during aging and disease. We will continue our molecular studies to determine
how PGC-1α binding to CBP80 controls gene transcription using cultured myoblasts and also skeletal
muscle regeneration in mice harboring five specific amino-acid changes in what we recently defined using
crystallography and functional assays as the CBP80-binding motif of PGC-1α. Aim 3 results from our
successful genetic screen for new proteins influencing the efficiency of NMD using insertional gene-trap
mutagenesis of haploid human cells that stably express an NMD reporter construct. We are validating
proteins of special interest and are working to understand how each affects NMD. In summary, by satisfying
previous aims, we have broadened the functional significance of NMD with the finding that NMD is hyper-
activated in FMRP deficiency. We have broadened the functional significance of NMD factors with the
finding that CBP80, which we have shown connects nuclear splicing to cytoplasmic translation via exon-
junction complexes and the pioneer round of translation, also functions in earlier gene-expression steps via
interactions with a transcriptional co-activator. We are also defining new effectors of NMD effici...

## Key facts

- **NIH application ID:** 10127344
- **Project number:** 3R01GM059614-22S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Lynne E Maquat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,228
- **Award type:** 3
- **Project period:** 1999-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127344

## Citation

> US National Institutes of Health, RePORTER application 10127344, Nonsense-mediated mRNA Decay and Nonsense-Mediated mRNA Decay Factors (3R01GM059614-22S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127344. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*