# Molecular mechanisms of RNA methyltransferases.

> **NIH NIH R35** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $246,500

## Abstract

Project Summary. This R35 MIRA application concerns investigating the structure, function, and regulation of
two mRNA methyltransferase enzymes: RNA (guanine-N7) methyltransferase (RNMT) and METTL3/METTL14.
The first RNA modification was identified in the early 1950s with the discovery of pseudouridine, followed some
years later by the identification of N6-methyladenosine (m6A) and N7-methylguanosine (m7G) in the 1970s.
Since then, over 150 RNA modifications have been discovered, with many more expected to be uncovered as
more sensitive and better tools for their identification are developed. As these modifications emerge,
researchers will need to uncover the protein machinery that writes and erases these marks, determine their
biological functions, and discern how they are regulated. Defects in the RNA modifications may lead to
diseases such as cancer, cardiovascular abnormalities, viral pathogenesis, or cognitive impairment. Therefore,
understanding the “code” and the enzymatic processes that govern the presence of RNA modifications are key
to revealing pathophysiological mechanisms and the development of novel therapeutics. The overall goal of
our research program is to understand the molecular mechanisms for how post-translational modifications
regulate the readers, writers, and erasers of RNA modifications, how these marks impact gene expression, and
how defects in this system contribute to disease. Many readers, writers, and erasers of RNA modifications
harbor PTMs, but our understanding of their influence on protein function is very limited. Therefore, we will use
a combination of protein semi-synthesis, enzymology, structural biology, mass spectrometry, and cell biology
strategies to unravel these novel regulatory mechanisms. In the next five years, we plan to investigate the
mechanistic basis for how RNMT and the METTL3/METTL14 complex are regulated by PTMs, with a long-term
vision of expanding to other readers, writers, and erasers in this family. RNMT catalyzes the methylation of the
5’cap of RNA, which is essential for transcript stability, splicing, nuclear transport, and cap-dependent
translation. RNMT and its interacting partner, RAM, are phosphorylated and ubiquitinated; however, the
molecular and structural details for their regulation and impact on biology are not well understood. The
METTL3/METTL14 complex methylates mRNA to generate N6-methyladenosine, which influences transcript
processing, stability, translation, and localization. The METTL3/METTL14 complex is regulated by arginine
methylation and ubiquitination; however, very little is known about how they impact the complex’s biochemical
and biological behavior. Therefore, we plan to assess the mechanistic and structural basis for how these
modifications regulate their biochemical and cellular functions using protein semi-synthesis. Furthermore, we
plan to characterize the ubiquitin E3 ligases that target these proteins for degradation and deubiquitinases that
reverse this...

## Key facts

- **NIH application ID:** 10938747
- **Project number:** 1R35GM155301-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Daniel R. Dempsey
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $246,500
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938747

## Citation

> US National Institutes of Health, RePORTER application 10938747, Molecular mechanisms of RNA methyltransferases. (1R35GM155301-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10938747. Licensed CC0.

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