# Protein Modification and Stability Regulation to Cope with Genotoxic Environments

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
Humans face many types of environmental genotoxic agents, such as various pollutants and radiation, that can
cause deleterious mutations and diseases. To survive and adapt to genotoxic conditions, cells rely on many
highly conserved and complex molecular strategies. One strategy to withstand genotoxic stress is the use of
error-prone repair mechanisms to increase mutation rates, which can potentiate new functions for better
adaptation to toxic environments. Another mechanism is the DNA damage checkpoint (DDC) system, which
controls the arrest and resumption of the cell cycle in accordance with the burden of genomic lesions. While
the frameworks of both strategies are largely established, important mechanistic details are lacking. To
address these gaps in knowledge, I will capitalize on the budding yeast model organism’s highly conserved
DDC and repair systems. Aim 1 will build on the recent observation that the desumoylase Ulp1 is sumoylated
upon genotoxin treatment and that mutating its two sumoylation sites results in a phenotype indicative of
increased homologous recombination (HR). I thus hypothesize that Ulp1 sumoylation suppresses HR to favor
error-prone repair. I will test this hypothesis and define the broader SUMO-based control of DNA repair
pathway usage in response to genotoxins. Aim 2 will address the recent findings that RPA is downregulated
after genotoxin exposure. I hypothesize that RPA downregulation can induce DDC recovery. To test this, I will
elucidate how RPA degradation is regulated and how this impacts DDC recovery. Defects in either of the DNA
repair pathway choices and DDC responses can lead to genome instability syndromes, characterized by
increased sensitivity to environmental genotoxins, developmental abnormalities, and increased tumorigenesis.
This work will lay the foundation for elucidating cellular adaptation strategies and can inform disease
prevention and treatment strategies. It will also provide important training for me to reach my long-term career
goal of becoming a principle investigator studying how human cells response to environmental genotoxins.

## Key facts

- **NIH application ID:** 10996289
- **Project number:** 1F31ES036884-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Tzippora Chwat-Edelstein
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2025-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996289

## Citation

> US National Institutes of Health, RePORTER application 10996289, Protein Modification and Stability Regulation to Cope with Genotoxic Environments (1F31ES036884-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10996289. Licensed CC0.

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