# Uncovering the impact of oxidative stress on centromere integrity

> **NIH NIH F31** · THOMAS JEFFERSON UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY
The centromere is a key region of the chromosome that mediates kinetochore assembly and spindle attachment,
thus ensuring proper chromosomal segregation. Compromised centromere integrity results in increased risk of
chromosomal rearrangements and mis-segregation, which can lead to chromosomal instability (CIN) and large-
scale genetic changes, characteristics commonly observed in cancer cells. One of the major threats to DNA
integrity and genome stability is oxidative damage arising from the exposure to reactive oxygen species (ROS),
known as oxidative stress (OS). Chronic exposure to OS is associated with centromeric dysfunction and
increased centromere instability, yet the impact of OS specifically at the centromere is unclear. To investigate
the DNA damage response at the centromere, our lab is using a specialized chemoptogenetic system designed
to generate the common OS induced lesion 8-oxoguanine locally at centromeric DNA. This lesion occurs
hundreds of times per day in a cell and is repaired through the Base Excision Repair (BER) pathway. My
preliminary studies revealed immediate BER factor recruitment as well as shifts in the cell cycle and a large
decrease in active DNA synthesis following OS at the centromere. In addition, I observed formation of DNA
breaks and an increase in apoptosis 24h after treatment. Finally, RNA sequencing revealed changes in genes
mapping to replication stress signaling and DNA damage repair. Based off these preliminary findings, I
hypothesize that OS at the centromere leads to replication stress and increased CIN. In Aim 1, I will
investigate the DNA damage response at the centromere and the contribution of DNA repair factors in
maintenance of centromere integrity. In Aim 2, I will assess the impact of centromeric damage on chromosome
segregation and DNA replication dynamics. These experiments will uncover the factors involved in mitigating the
impact of OS and maintaining integrity at centromeres. The results will provide insight into how centromere
dysfunction and subsequent CIN arise, helping further our knowledge of CIN associated cancers and informing
potential therapeutic targets.

## Key facts

- **NIH application ID:** 10998118
- **Project number:** 1F31ES036105-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Lily Thompson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998118

## Citation

> US National Institutes of Health, RePORTER application 10998118, Uncovering the impact of oxidative stress on centromere integrity (1F31ES036105-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10998118. Licensed CC0.

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