# RNA Modifications and Turnover during Viral-induced Decay

> **NIH NIH R35** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2024 · $398,750

## Abstract

PROJECT SUMMARY
Under stress conditions, the cells needs to rapidly respond to environmental clues to adapt the gene
expression landscape. One particular aspect of the gene expression cascade that is emerging as a prime
source for this rapid change is the manipulation of RNA turnover. Yet, what dictates RNA decay or stability in a
time-sensitive and fast manner is not fully understood. In the recent years, post-transcriptional modifications
have emerged as potent and dynamic regulator of a range of RNA functions including RNA stability. However,
little is known about the regulation of post-transcriptional modifications in stress conditions or in response to
rapid changes in gene expression. This proposal focuses on the post-transcriptional RNA modification N6-
methyladenosine (m6A) and aims to determine how m6A status may control RNA fate in the face of
widespread RNA decay. Our central hypothesis is that this modification helps discriminate mRNAs that are
targeted for fast degradation from those that are spared. To test this hypothesis, we are using a powerful tool
as we are taking advantage of a very potent viral nuclease. This endonuclease comes from the KSHV virus
(Kaposi's Sarcoma Associated Herpesvirus) and has the ability, by itself, to trigger up to 80% of total mRNA
degradation in mammalian cells. However, to date, it is unclear what renders an mRNA susceptible or resistant
to this pervasive nuclease. In this proposal, we will use this viral system to query the host transcriptome
response to this massive RNA decay event. We will combine RNA-seq and m6A-RIP seq strategies to assess
how diverse the m6A landscape is among degraded or spared mRNAs. We will then monitor how the m6A
machinery responds and/or is affected this re-structuring of the RNA steady state in the cell. In particular, our
emphasis will be on the m6A readers that may directly be involved in decoding the m6A marks on the stable
mRNAs. Finally, because RNA decay under stress conditions and/or in response to external stimuli is an
heterogenous process, we will expand our exploration of m6A regulation of RNA stability to other sources of
RNA degradation beyond viral nucleases using a novel site directed CRISPR Cas system. Taken together, we
anticipate that these studies will shed light on a novel type of sensing mechanism that adapts the host cell
environment to large changes in RNA stability. Since the regulation of RNA turnover is at the core many
processes in the cell, understanding how post-transcriptional modifications may contribute to this complex
balance should reveal novel pathways both in pathogenic and normal cells.

## Key facts

- **NIH application ID:** 10840937
- **Project number:** 5R35GM138043-05
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** Mandy Muller
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $398,750
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840937

## Citation

> US National Institutes of Health, RePORTER application 10840937, RNA Modifications and Turnover during Viral-induced Decay (5R35GM138043-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10840937. Licensed CC0.

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