# Mechanisms of aberrant ribosomal RNA (rRNA) methylation and altered mRNA translation in cancers

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $354,563

## Abstract

Project Summary
The fidelity of mRNA translation is essential to maintain cellular homeostasis and prevent the production of
aberrant proteins that could lead to disease development. Ribosomes are key components of the core
translational machinery whose activity can be modulated by diverse types of nucleotide methylation on the
ribosomal RNA (rRNA). A growing body of evidence indicates that the pattern of rRNA methylation is altered in
cancers, leading to the synthesis of specialized ribosomes with the unique ability to translate mRNAs coding
for oncogenic proteins. rRNA methylation has been shown to dynamically regulate ribosome function and
influence their efficiency, accuracy and affinity for certain type of mRNAs. Hence, pathways regulating rRNA
methylation can selectively drive the translation of a proteome that supports cellular transformation and tumor
development. Our overarching goal is to identify pathways and key players involved in regulating the aberrant
methylation of rRNA in cancers as they represent unexploited therapeutics targets. We recently uncovered that
the oncogene Pelp1 is an important regulator of rRNA methylation in cancer cells. Our experimental approach,
supported by preliminary data, is to elucidate the mechanisms by which Pelp1 regulates rRNA methylation and
demonstrate the importance of this process for cancer progression. We hypothesize that Pelp1 supports
tumorigenesis by modulating ribosomes translational activity through its ability to regulate rRNA methylation. In
Aim1 we will determine whether Pelp1 regulates rRNA methylation by recruiting RNA methyltransferases to the
nascent rRNA transcript. Because rRNA methylation plays an important role in regulating the translational
capacity of ribosomes, we will assess whether overexpression of Pelp1 changes ribosome efficiency, fidelity,
and affinity for certain types of mRNAs using translation reporter assays and a polysome profiling-sequencing
approach (Aim 2). Pelp1 is overexpressed in 60-80% of breast cancers, where its level of expression directly
correlates with tumor grade, metastasis, and endocrine therapy resistance. In Aim 3, we will use orthotopic
mouse model of breast cancer to assess whether the ability of Pelp1 to regulate rRNA methylation is required
to support tumorigenesis. Our findings suggest that by regulating rRNA methylation, Pelp1 participates in the
translational reprograming of cancer cells, thereby promoting the selective translation of oncogenic genes. The
successful completion of our proposed study will yield important insight into mechanisms of aberrant mRNA
translation and it roles in oncogenesis.

## Key facts

- **NIH application ID:** 9876919
- **Project number:** 5R01CA230746-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Catherine Denicourt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,563
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876919

## Citation

> US National Institutes of Health, RePORTER application 9876919, Mechanisms of aberrant ribosomal RNA (rRNA) methylation and altered mRNA translation in cancers (5R01CA230746-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9876919. Licensed CC0.

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