# New Mechanisms of the Pseudouridine Synthase Module in Mitoribosome Assembly

> **NIH NIH R35** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2024 · $402,498

## Abstract

PROJECT SUMMARY/ABSTRACT
RNA modifiers coordinate essential steps of the mitochondrial ribosome assembly pathway; yet our
limited understanding of the signals controlling these RNA editing factors hinders our knowledge of how
these important regulators misshape the mitochondrial proteome in complex diseases. In mammals,
the RPUSD4 pseudouridine (Y) synthase collaborates with newly identified auxiliary factors to catalyze
pseudouridylation of mitochondrial ribosomal RNA (rRNA). Although the factors necessary for
mitochondrial rRNA pseudouridylation have been annotated, the molecular mechanisms by which the
Y synthase module exerts exquisite specificity towards assembling mitochondrial ribosomes is
unknown. Moreover, mounting evidence links dysregulated rRNA pseudouridylation to mitochondrial
genetic disorders, underscoring the importance of this underexplored RNA modification regulatory
network. To address these shortcomings, we will apply a cross-disciplinary program combining hybrid
structural biology, genomics, and biochemistry. This integrative approach will address critical questions
in mitochondrial RNA processing, including: 1) How does the RPUSD4 Y synthase exerts strict
specificity for its single rRNA modification site? 2) Why do mitochondrial disease-mutations dysregulate
the Y synthase module? 3) How does the Y synthase module recognize assembling ribosomes?
Defining the intricate molecular signals coordinating the fundamental process of rRNA
pseudouridylation will set a framework to launch innovative programs that exploit mitochondrial RNA
processing systems for the benefit of mitochondrial disease patients.

## Key facts

- **NIH application ID:** 11263790
- **Project number:** 7R35GM147123-04
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Monica Pillon
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,498
- **Award type:** 7
- **Project period:** 2022-08-05 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11263790

## Citation

> US National Institutes of Health, RePORTER application 11263790, New Mechanisms of the Pseudouridine Synthase Module in Mitoribosome Assembly (7R35GM147123-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11263790. Licensed CC0.

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