# Regulation of Mammalian mRNA Decay

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2021 · $55,640

## Abstract

Summary of the funded parental grant GM067005:
The control of mRNA stability is a critical determinant in the post-transcriptional regulation
of eukaryotic gene expression. Even minor alterations in mRNA stability can have
profound consequences and may manifest as clinical phenotypes as illustrated by the
ability of aberrantly expressed proto-oncogenes that can give rise to malignancies.
Eukaryotic mRNAs are generally thought to possess an N7 methyl guanosine (m7G) cap
at their 5¢ end to promote their stability and translation. However, our recent
demonstration that mammalian mRNAs can also carry a 5´-end nicotinamide adenine
dinucleotide (NAD) cap that in contrast to the m7G cap promotes mRNA decay, provides
a new paradigm for mRNA 5´ end processing and the contribution of nucleotide
metabolites in mRNA turnover. We now demonstrate that the redox state of NAD can also
modulate 3´ RNA decay with free NAD functioning as a cofactor to enhance RNA decay
and potentially providing a link to cellular energetics. Moreover, flavin adenine
diphosphate (FAD) can also serve as a 5´ cap on mammalian RNAs with Nudt16 and
DXO hydrolases functioning as proteins that can remove the FAD cap (deFADding) in
vitro. We will build on these novel findings throughout this proposal within three specific
aims. The first will address the functional role of free NAD on the control of 3´ end RNA
decay in vitro and delineate the molecular mechanism involved in its stimulation of decay.
The second will deduce changes in mRNA decay as a consequence of altered NAD levels
in cells and assess the regulatory role imparted by stress conditions in modulating RNA
decay through the control of NAD levels. In the last aim, we establish FAD cap as an
alternative RNA cap, identify FAD-capped RNAs and decipher the role of FAD caps and
the deFADding enzymes in cells. Collectively, the proposed studies will provide insight
into a heretofore unknown fundamental post-transcriptional regulatory mechanism and
will provide the framework for potential novel avenues to control gene expression in
normal and disease states.

## Key facts

- **NIH application ID:** 10387387
- **Project number:** 3R01GM067005-15S1
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** MEGERDITCH KILEDJIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $55,640
- **Award type:** 3
- **Project period:** 2004-09-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387387

## Citation

> US National Institutes of Health, RePORTER application 10387387, Regulation of Mammalian mRNA Decay (3R01GM067005-15S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10387387. Licensed CC0.

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