# Understanding the variability in nonsense-mediated RNA decay

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2020 · $41,209

## Abstract

PROJECT SUMMARY
The goal of my research program is to understand how cells detect and degrade aberrant RNAs,
and how this surveillance process shapes gene expression. Nonsense-mediated RNA decay
(NMD) is an evolutionarily conserved surveillance process that safeguards cells against RNAs
that carry nonsense mutations and their truncated translation products. During NMD, a ribosome
engaged in translating an aberrant mRNA terminates prematurely. Factors downstream of the
prematurely terminating ribosome recruit NMD machinery and initiate destruction of the aberrant
mRNA. As a result, nonsense mutations often render a gene nonfunctional due to the rapid
degradation of its mRNA transcripts. We and others have shown that the efficiency of NMD varies
widely across different genetic and cellular contexts, but the mechanisms that cause this
variability remain poorly understood. By investigating nonsense genetic variants that have risen
to high frequency in the healthy human population, I have demonstrated that over half of these
common nonsense variants escape NMD via mechanisms that include stop codon readthrough
and translation reinitiation. These results highlight our incomplete understanding of the range of
molecular mechanisms that could rescue gene function in the presence of a predicted “loss of
function” mutation. My research program builds on these novel discoveries to systematically
investigate cis and trans factors that allow an mRNA to escape NMD. We will combine massively
parallel reporter assays with targeted genetic screens to identify consensus sequence and/or
structural features that permit stop codon readthrough and reinitiation. We will complement these
approaches with in vivo genome editing to perturb sequence features that promote NMD escape
of validated candidates of readthrough or reinitiation. We will use validated sequences that
escape NMD to identify trans factors via genetic screens and/or affinity isolation followed by mass
spectrometry. Given the role of NMD in shaping gene expression, understanding the mechanisms
that cause NMD efficiency to vary has immense practical significance in both precision medicine
initiatives and in basic biomedical research.

## Key facts

- **NIH application ID:** 10046108
- **Project number:** 3R35GM133433-01S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Sujatha Jagannathan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $41,209
- **Award type:** 3
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046108

## Citation

> US National Institutes of Health, RePORTER application 10046108, Understanding the variability in nonsense-mediated RNA decay (3R35GM133433-01S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10046108. Licensed CC0.

---

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