# Nucleolar signaling in cancer

> **NIH NIH R03** · ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED · 2020 · $80,500

## Abstract

Project Summary/Abstract
The nucleolus is a cellular organelle that carries out the synthesis of ribosomes and has a multitude of sensory
and regulatory functions in the cell. Interference with biosynthetic processes in the nucleolus triggers a p53-
dependent nucleolar stress response that promotes cell death in some contexts but can be cytoprotective in
others, leading to increased cell resistance to genotoxic drugs. The regulatory functions of the nucleolus are
thus important for understanding tumor responses to chemotherapy agents, but how exactly nucleolar stress
influences therapeutic outcomes is not known. Our recent studies suggest that nucleolar stress may cross-
activate components of the DNA damage response (DDR) pathway that helps to maintain genome integrity.
We hypothesize that the capacity of the nucleolus to engage the DDR machinery is important for the timely
activation of cellular defense mechanisms essential for cell survival. This proposal focuses on the signaling link
between the nucleolus and the ATM protein kinase, a key mediator of the DDR. Using our previously
developed cell models for the conditional inhibition of specific ribosome biosynthesis steps, we will determine
whether ATM activation during nucleolar stress occurs in a similar or different way compared with its activation
by DNA damage and oxidative stress. We will also examine chromatin markers associated with the stressed
nucleolus and their possible colocalization with ATM complexes. Finally, profiling transcriptome changes in
ATM-proficient and deficient cells will be used to assess the biological role of ATM in the nucleolar stress
response. This study will advance our understanding of the signaling mechanisms induced by nucleolar stress.
The generated knowledge will be important as it can be applied to increase the differential margins of drug
sensitivity in normal and tumor cells and thus improve the efficacy of therapeutic interventions in cancer
patients.

## Key facts

- **NIH application ID:** 9881762
- **Project number:** 1R03CA246009-01
- **Recipient organization:** ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
- **Principal Investigator:** DIMITRI G PESTOV
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $80,500
- **Award type:** 1
- **Project period:** 2019-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881762

## Citation

> US National Institutes of Health, RePORTER application 9881762, Nucleolar signaling in cancer (1R03CA246009-01). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9881762. Licensed CC0.

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