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

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $10,600

## Abstract

This competitive renewal 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 effect...

## Key facts

- **NIH application ID:** 10385083
- **Project number:** 3R01GM059614-23S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Lynne E Maquat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $10,600
- **Award type:** 3
- **Project period:** 1999-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385083

## Citation

> US National Institutes of Health, RePORTER application 10385083, Nonsense-Mediated mRNA Decay and Nonsense-Mediated mRNA Decay Factors (3R01GM059614-23S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10385083. Licensed CC0.

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