# Chromatin mobility in response to DNA damage

> **NIH NIH U01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $601,304

## Abstract

Project Summary
Genomic translocations are well-established drivers of therapy-related myeloid neoplasms (t-MN) that affect
survivors of primary malignancies. t-MN accounts for 10-20% of all myeloid malignancies and have very poor
clinical outcomes. It is not possible to predict which patients treated for a primary cancer will develop t-MN,
which constitutes a major clinical challenge. A method to assess the risk of translocations after patient
exposures to DNA damaging chemotherapy and radiations would inform therapeutic decisions. Translocations
depend on the movements of broken DNA ends on non-homologous chromosomes. We developed a method
based on diffractive optical elements (DOE) to track photoactivated chromatin reporters (PACR) and map
chromatin motions in the cell nucleus. Our preliminary data show that chromatin movements transiently
decrease in response to DNA damage, which led to the hypothesis that chromatin `freezes' to facilitate the
initial steps of the DNA damage response and reduce frequencies of genomic rearrangements. This effect may
be mediated by reversible chromatin compaction and by chromatin interactions with structural nuclear
elements. Inter-individual variability may determine genomic aberration frequencies and t-MN risk. The
following specific aims will expand PACR assays and test this hypothesis: In Aim 1, methodology will be
developed for 3D measurements of chromatin mobility, in order to improve tracking accuracy and to account
for inhomogeneities of the nuclear environment in all three dimensions. Rapid light sheet imaging will be used,
and a novel multifocus 3D system based on a rotating point spread function DOE will be built. New
photoactivatable DNA dyes will be developed to expand the PACR approach to difficult-to-transfect cells and
tissues. The goals for Aim 2 are to identify the mechanisms controlling chromatin motions after DNA damage
and to assess the functional consequences for DNA repair and translocations of chromatin `freezing'. We will
feed PACR measurements with high time resolution (before/during/after DNA damage) into biophysical
polymer models to predict physical changes of chromatin (intramolecular forces, persistence length, etc.), then
test the predictions using multidimensional maps of chromatin motions, compaction, and nucleoskeletal
organization, as well as functional cell assays. Two approaches to alter chromatin diffusion will assess
causality between chromatin motions, DNA repair, and genomic translocations. In Aim 3, we will use
hematopoietic stem/progenitor cell samples from t-MN patients and healthy donors to test for clinically relevant
associations between chromatin motions and genomic translocations. Characterizing the physical origins of
genomic translocations may yield new methods to predict, and new targets to prevent, genomic
rearrangements driving cancer initiation. Beyond the proposed research focused on chromatin motions during
DNA repair, we anticipate broad applicability o...

## Key facts

- **NIH application ID:** 10242769
- **Project number:** 5U01CA214282-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Keith D Bonin
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $601,304
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242769

## Citation

> US National Institutes of Health, RePORTER application 10242769, Chromatin mobility in response to DNA damage (5U01CA214282-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242769. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*