# Noncanonical E2F Regulation in the Neuronal DNA Damage Response

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $53,894

## Abstract

PROJECT SUMMARY/ABSTRACT
 The E2F transcriptional program, which controls cell cycle commitment and progression in proliferating
cells, is upregulated following DNA damage in neurons. Neuronal DNA damage and cell cycle dysregulation
are features of neurodegeneration that have also been associated with psychiatric diseases. Although the
function of E2F during proliferation has been extensively studied, the role of E2F in nonproliferating cells, such
as in neurons, has received less attention. Emerging evidence indicates that E2F plays a role in DNA damage
repair, independent of its role in cell cycle entry. This role may be especially important in neurons, which are
uniquely vulnerable to DNA damage. Although E2F induction has been linked to resolution of DNA damage in
bulk-cell preparations of neurons, such bulk analyses fail to account for potentially confounding heterogeneity
within samples. Single cell analysis is necessary to examine the relationship between E2F activity and DNA
damage and to link E2F dynamics to functional outcomes in the same cells.
 The Meyer Lab specializes in single-cell analysis of high-throughput microscopy data, and the lab has
recently developed a fluorescent biosensor of E2F activity for this purpose. Quantitative microscopy using live-
and fixed-cell readouts of E2F activity and DNA damage will allow signaling history to be mapped to cell fate
outcomes at single-cell resolution in thousands of cells. My hypothesis is that in postmitotic neurons, E2F is
reversibly activated to drive DNA repair without DNA replication following sublethal DNA damage; however, if
DNA damage activates E2F beyond the threshold for S-phase entry, E2F induces DNA replication and
apoptosis. By characterizing how the E2F program is regulated in neurons and how it contributes to DNA
damage repair, this study will support the identification of potential treatment targets for preserving genetic
integrity in brain disorders characterized by genotoxic stress.
 This research project represents an important component of my training for a career as an independent
investigator, employing high-throughput single-cell methods to study the biology of complex diseases. My long-
term goal is to become a physician-scientist, practicing as a psychiatrist while also running a basic science lab
in an academic hospital. The plan outlined in this proposal along with the mentorship of my sponsor, thesis
committee, and the leadership of the Tri-I MD- PhD program, will help me achieve these career aspirations.

## Key facts

- **NIH application ID:** 10844374
- **Project number:** 5F30MH132311-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** David Leon Rosenthal
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,894
- **Award type:** 5
- **Project period:** 2023-05-15 → 2026-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844374

## Citation

> US National Institutes of Health, RePORTER application 10844374, Noncanonical E2F Regulation in the Neuronal DNA Damage Response (5F30MH132311-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10844374. Licensed CC0.

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