# Defining the quantitative relationship between DNA damage and cell cycle dynamics in CUL9-deficient cells

> **NIH NIH F30** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $46,204

## Abstract

PROJECT SUMMARY/ABSTRACT
 Genome instability and cell cycle dysregulation are two important yet unique hallmarks of cancer, as
they can accelerate acquisition of other tumorigenic mutations and thus the development of cancer. While the
molecular functions and signaling pathways of both hallmarks have been extensively investigated, the
quantitative and continuous interplay between DNA damage and the cell cycle is unclear. Understanding the
direct interrelationship requires precise quantitative measurements of cell cycle transitions and DNA damage
throughout the cell cycle in the same cell. Gaining this quantitative understanding will yield translational
insights, as the efficacy of many chemotherapeutics and radiation therapies require precise dosage levels (to
induce appropriate amounts of DNA damage) and treatment schedules (to target specific phases of the cell
cycle). My overall objective is to understand how DNA double strand breaks (DSBs), the most harmful form of
DNA lesions, affect cell cycle progression; and how the cell cycle program conversely regulates repair of
DSBs. To achieve this objective, I propose to combine quantitative dynamic measurements of DSBs and cell
cycle progression in single cells. I will use live-cell imaging, computational modeling, and manipulation of DNA
damage to elucidate the molecular mechanisms that interlink DSB dynamics and cell cycle outcomes.
 I will focus my investigation specifically on DNA damage that arises from loss of CUL9, an E3 ubiquitin
ligase and tumor suppressor. We previously found that loss of CUL9 increases the frequency of spontaneous
DSBs in a subpopulation of unperturbed cells. How DSBs arise in this context and how they affect cell cycle
progression is not known. Using time-lapse fluorescence microscopy with a 53BP1 live-cell reporter for DSBs,
I discovered a striking trend in which 53BP1 foci are absent ~6 hours before cytokinesis in unperturbed cells.
This pattern was disrupted in CUL9-deficient cells. Based on my preliminary data, my central hypothesis is
that CUL9 facilitates the coordination of DSB repair and cell cycle progression. To test my hypothesis, I
propose two specific aims: Aim 1: Determine how the dynamics of DSBs affect cell cycle progression and
define the role of CUL9 in this relationship. This aim uses quantitative approaches and computational
modeling to understand how DSBs slows cell cycle progression in a phase-specific way and determine how
this regulatory relationship depends on CUL9. Aim 2: Determine the cell cycle regulation of DSB repair
protein 53BP1 recruitment to DSBs, and if this regulation depends on CUL9. This aim characterizes 53BP1
recruitment to sites of DSBs at the late S/G2 phase and asks how CUL9 governs this process.
 This proposed research is innovative in its quantitative, single live-cell approach and is significant
because the computational model to be developed will provide insights into novel treatment strategies against
cancer. In the contex...

## Key facts

- **NIH application ID:** 9932348
- **Project number:** 5F30CA213876-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Hui Xiao Chao
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $46,204
- **Award type:** 5
- **Project period:** 2017-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932348

## Citation

> US National Institutes of Health, RePORTER application 9932348, Defining the quantitative relationship between DNA damage and cell cycle dynamics in CUL9-deficient cells (5F30CA213876-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932348. Licensed CC0.

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