# Protein RNA Rearrangements in the Spliceosome

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $554,371

## Abstract

ABSTRACT
 Excision of introns from precursor messenger RNA by the spliceosome is a critical step in almost all
human gene expression. This process is highly regulated, integrally linked with the transcription of genes and
other processing events, such as polyadenylation and nucleotide modification.
 The mechanism by which the spliceosome recognizes the exact sites for the chemical events and how
the reactions are catalyzed are not well understood. The long-term goals of this project are to understand
interactions and rearrangements between spliceosome components and the RNA ligands that are substrates
for the catalytic reactions. Ample evidence argues for multiple rearrangements of factors and multiple
recognition events at the branch site. Investigation of these events — which are not understood
mechanistically — will elucidate interactions and rearrangements among core components and may serve as a
paradigm for rearrangements in the spliceosome and in other RNP machines. This proposal focuses on
mechanisms by which spliceosomal dynamics impact splicing fidelity.
 The Aims of this project focus on two newly-discovered aspects of the spliceosome and snRNAs:
(1) We will investigate the role of inositol hexakisphosphate (IP6) in spliceosome function. This small molecule
was recently identified unexpectedly by cryo-EM as part of splicing complexes. No biochemistry or genetics
has so far explored its importance. We use mutants in the IP6 biosynthetic pathway to explore its contribution
to splicing and whether inositol polyphosphate (IPP) isoform levels may influence splice events. (2) One hole
in our current understanding of RNA biology is the role of snRNA mutations in disease. Two mutations were
recently described in the 5'-end of U1 snRNA, associated with glioblastoma (GBM) and other cancers. We will
use our in silico snRNA genome to interrogate TCGA whole genome datasets (WGS) and investigate, in
particular, U2 snRNA mutations that we find highly enriched in bladder cancer and bladder cancer organoid
lines.

## Key facts

- **NIH application ID:** 10367405
- **Project number:** 2R01GM057829-24A1
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** CHARLES C QUERY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $554,371
- **Award type:** 2
- **Project period:** 1999-08-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367405

## Citation

> US National Institutes of Health, RePORTER application 10367405, Protein RNA Rearrangements in the Spliceosome (2R01GM057829-24A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10367405. Licensed CC0.

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