# Catalytic roles of RNA methyltransferase DIMT1

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $601,932

## Abstract

Ribosome RNA (rRNA) modifying enzymes are important factors in the assembly and function of
ribosomes, dysregulation of which is frequently seen in human hematopoietic disorders. We only have limited
knowledge of the catalytic role of rRNA modifying enzymes in the physiological and pathological processes of
human hematopoiesis, although a few studies characterized the importance of rRNA modifications in these
processes. Preliminary data (CRISPR screening) from my laboratory shows that the ablation of DIMT1 (an 18S
rRNA Ni·6A-dimethylation (mi·6A) methyltransferase) significantly impairs cell viability of hematopoietic stem
progenitor cells (HSPCs). DIMT1 is highly expressed in HSPC, and its expression decreases in the differentiated
lineages. However, the molecular function and detailed mechanism of DIMT1 in human hematopoiesis remain
elusive. Even though DIMT1-mediated rRNA modifications are highly conserved, the catalytic activity of
DIMT1 is dispensable for proper ribosome biogenesis. However, our recent results suggest that the catalytic
activity of DIMT1 is required for the viability of HSPCs, while the catalytic-independent role of DIMT1 is important
for 18S rRNA processing and ribosome biogenesis. This implies that DIMT1 may have a necessary role as a
scaffold in ribosome biogenesis separate from its catalytic activity. Furthermore, we show that the catalytic role
of DIMT1 is indispensable for the expression of genes involved in the Fanconi anemia and other DNA repair
pathways. However, whether and how DIMT1-mediated mi·6A installation in 18S rRNA influences cell viability
and DNA repair pathways in HSPCs are not known. Here, our goal is to understand the molecular function and
the mechanistic details of the catalytic role of DIMT1 in the regulation of cell viability and gene expression in
HSPCs. Specifically, Aim 1 will investigate the catalytic role of DIMT1 as an 18S rRNA methyltransferase in
HSPC cell viability and protein synthesis. Aim 2 will investigate the molecular mechanism by which DIMT1-
mediated m26•6A in 18S rRNA controls translation elongation using an in vitro eukaryotic translation system. Aim
3 will investigate the structure-function relationships and catalytic mechanism of DIMT1. Results from these
studies will provide novel insights into how the catalytic role of DIMT1 impacts HSPC cell viability and the
expression of genes Fanconi anemia and other DNA repair pathways. The understanding we will gain can be
broadly applicable to hematopoietic studies and many other biological disciplines.

## Key facts

- **NIH application ID:** 10522085
- **Project number:** 1R01HL160726-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** BARRY S. COOPERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $601,932
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522085

## Citation

> US National Institutes of Health, RePORTER application 10522085, Catalytic roles of RNA methyltransferase DIMT1 (1R01HL160726-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10522085. Licensed CC0.

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