# Mechanisms and functional implications of SARS-CoV-2 mRNA capping and modification.

> **NIH NIH R21** · COLORADO STATE UNIVERSITY · 2020 · $407,060

## Abstract

SARS-CoV-2 must cap and methylate its mRNAs to ensure their stability, translatability, and avoid
detection by host innate immune mechanism as non-self transcripts. The process of RNA capping, therefore,
is pivotal to the success of a SARS-CoV-2 infection. It also represents a key contributor to the molecular
mechanisms of pathogenesis as well as a very attractive target for the development of antiviral therapeutics.
However, there are three key knowledge gaps that have slowed progress in our understanding of this
important area of coronavirus molecular biology that will be addressed in this proposal. First, the identity of the
guanylyltransferase (GTase), the centerpiece of the viral RNA capping machinery that transfers GTP to the 5'
end of the nascent transcript, is unknown. We will use a two-pronged strategy of complementary molecular
and biochemical approaches to address this glaring gap in our understanding of SARS-CoV-2 mRNA capping
mechanisms, laying the foundation for the development of capping-targeted antivirals. Second, while RNA
capping is a regulated process and uncapped RNAs play an influential role in the biology of other positive
sense RNA viral infections, it is not known if RNA capping is a regulated or a default event in coronaviruses.
We will determine if uncapped RNAs are produced by SARS-CoV-2 in order to establish the foundation for a
role of regulated capping and non-coding viral transcripts in SARS-CoV-2 infections. Finally, every cellular
mRNA that begins with a terminal adenosine has that residue 2'O methylated at the ribose ring as well as N6
methylated on the adenosine base (m6Am). The strong conservation of this m6Am modification indicates its
importance in cell biology, an assertation recently confirmed with data suggesting that the modification
increases translatability and facilitates recognition of the transcript as `self'. Interestingly, SARS-CoV-2 and
other coronaviruses all initiate their transcripts with an A residue, but it is not known whether that A residue
contains an m6A modification. In the final part of this project, we will determine the m6A modification status of
the terminal 5' A residue of SARS-CoV-2 mRNAs and investigate the role that the modification (or lack thereof)
plays in the biology of coronaviral transcripts. Collectively these studies will provide important new insights into
the molecular biology of SARS-CoV-2 and open up avenues for the development of broad-spectrum anti-
coronaviral therapeutics.

## Key facts

- **NIH application ID:** 10185716
- **Project number:** 1R21AI158335-01
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Brian Geiss
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,060
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185716

## Citation

> US National Institutes of Health, RePORTER application 10185716, Mechanisms and functional implications of SARS-CoV-2 mRNA capping and modification. (1R21AI158335-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10185716. Licensed CC0.

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