# Project 3: Oncogene Activation and DNA Damage Response-Mediated Epigenetic Changes

> **NIH NIH P01** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2021 · $350,861

## Abstract

This proposal is based on the novel finding that in addition to activating downstream components of the DNA
damage response (DDR), the Mre11 complex-ATM arm of the DDR is required to activate a p53-dependent
epigenetic program in response to oncogene activation. This pathway appears to parallel that governed by
Ink4a-p19Arf. We will carry out quantitative analysis of the abundance and location of chromatin marks arising
in response to the activation of neuT and c-myc, and assess changes in the expression of chromatin modifying
enzymes in epithelial cells. To determine whether these responses are shared by hematopoietic cells, we will
examine the same endpoints as well as the onset and progression of malignancy in p53-/- and Mre11ATLD1/ATLD1
bone marrow following introduction of c-myc or the Nup98-Hox9a cDNA. Finally, having defined these features
of the p53-dependent epigenetic response to oncogene, we will identify enzymes that mediate this response
and test the hypothesis that this p53-dependent function which requires DDR signaling is tumor suppressive.
Collectively, the experiments proposed will illuminate a previously undescribed connection between p53 and
the upstream components of the DDR that effects a barrier to oncogene-driven carcinogenesis. Therefore, this
proposal is highly significant with the potential to provide novel mechanistic insight regarding tumor
suppression by p53.

## Key facts

- **NIH application ID:** 10132252
- **Project number:** 5P01CA087497-20
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** John HJ Petrini
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $350,861
- **Award type:** 5
- **Project period:** 2000-09-30 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132252

## Citation

> US National Institutes of Health, RePORTER application 10132252, Project 3: Oncogene Activation and DNA Damage Response-Mediated Epigenetic Changes (5P01CA087497-20). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10132252. Licensed CC0.

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