# Defining the DNA damage pathway in faithful mitotic progression

> **NIH NIH K22** · YALE UNIVERSITY · 2021 · $186,192

## Abstract

PROJECT SUMMARY/ABSTRACT
 Genomic instability is a hallmark of cancer and correlated with overall poor patient prognosis. A specific
form of genomic instability is chromosomal instability (CIN), which occurs when a cell continuously missegregate
their chromosomes leading to changes in karyotype. CIN is a common feature of cancer – with approximately
90% of solid tumors and 50% of hematopoietic cancers exhibiting CIN. CIN is also correlated with increased
tumor progression and poor patient prognosis. However, the levels of CIN must be maintained at an optimal
level, because too high levels of missegregation events are deleterious to cells. This creates a therapeutic
window by which chemotherapies can exploit CIN to create effective treatments against cancer cells. ATR, a
master regulator of DNA damage repair pathways, ensures genomic stability by promoting DNA damage repair
and timely replication. I recently showed that ATR also promotes genomic stability by promoting faithful
chromosome segregation in mitosis and preventing CIN. In this application, I propose to investigate the
mechanism by which ATR is activated in mitosis (Aim 1), identify its substrate network (Aim 2) and use ATR
inhibition to target CIN cancer cells specifically (Aim 3). My proposed studies may reveal more novel functions
of ATR in mitosis and allow us to better understand of how mitotic processes are regulated by ATR and other
DDR proteins to ensure proper chromosome segregation. This in turn, will give us a better understanding of the
overlap of mitotic and DDR proteins in ensuring genomic stability. Lastly, I hope that developing a strategy to
specifically kill CIN cancer cells will be a breakthrough in targeted cancer therapies.
 My career goal is to obtain a research faculty position at a leading institution where I will dissect the
mechanisms by which ATR and other DDR proteins regulate chromosome segregation. My successful transition
would be bolstered by augmenting my expertise in cell biology, mass spectrometry and mouse cancer models.
I will use these acquired skills to investigate whether ATR inhibitors can be used to specifically target CIN cancer
cells. Importantly, the protected time that this award provides me will allow me to elucidate the mechanism by
which ATR is activated and determine if ATR inhibitors can be used to exploit CIN in cancer cells. Furthermore,
the success of this project will be greatly enhanced by the outstanding collaborators that I will have advise me
through the K22 period. The receipt of this award will allow me to expand my research plan and establish myself
as a primary investigator in the field of cancer biology.

## Key facts

- **NIH application ID:** 10177975
- **Project number:** 5K22CA244865-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Lilian Carolina Kabeche
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $186,192
- **Award type:** 5
- **Project period:** 2020-06-02 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177975

## Citation

> US National Institutes of Health, RePORTER application 10177975, Defining the DNA damage pathway in faithful mitotic progression (5K22CA244865-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10177975. Licensed CC0.

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