# Roles of nuclear architecture and phase separation in heterochromatin repair dynamics

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $339,358

## Abstract

SUMMARY
Advancing our knowledge of pericentromeric heterochromatin repair is a high impact investment for improving
human health: heterochromatin is a poorly characterized region that comprises nearly a third of the human
genome; double-strand break (DSB) repair failures in this region affect not just specific genes, but also
genome-wide stability; and the likelihood of failures is high because of the many repeated sequences that
characterize this domain. Despite the foundational importance of characterizing these processes, DSB repair
mechanisms in heterochromatin are largely understudied. We discovered a specialized pathway that promotes
faithful homologous recombination (HR) repair in heterochromatin while preventing aberrant recombination,
effectively isolating heterochromatic repair sites to the nuclear periphery before strand invasion. We have
recently identified several components required for this process, including nuclear actin filaments (F-actin) an
myosins, and chromatin-associated nucleoporins, but the regulation and function of these components remain
poorly understood. Deregulation of heterochromatin repair is likely one of the most underestimated and
powerful sources of tumorigenesis, and identifying the components involved is essential for understanding
cancer etiology and developing more effective strategies for therapeutic intervention. Our central hypothesis is
that F-actin, myosins, nucleoplasmic nucleoporins, and phase separation are essential regulators of
heterochromatin repair dynamics, and that SUMOylation participates in coordinating their function repair
progression. We will combine a wealth of super resolution imaging, genetic and biochemical approaches to
investigate the molecular mechanisms involved in these process. Expected positive outcomes of this research
include the systematic identification of the molecular machinery that protects heterochromatin from massive
genome rearrangements, enabling successful completion of HR repair. These studies are also expected to
illuminate missing links between nuclear architecture and dynamics, phase separation, repair progression, and
the stability of repeated DNA sequences. These results will have an important positive impact by identifying
crucial safeguard mechanisms used by normal cells to protect the genome from environmental threats.
Mutations in these pathways result in genome instability, tumorigenesis, and reduced life span. Thus, we
expect that the proposed studies and future research will trigger exciting advancements in the prevention, early
detection, and treatment of cancer and other human diseases associated with genome instability and aging-
related disorders.

## Key facts

- **NIH application ID:** 10694860
- **Project number:** 5R01GM117376-09
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Irene E Chiolo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $339,358
- **Award type:** 5
- **Project period:** 2015-09-17 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694860

## Citation

> US National Institutes of Health, RePORTER application 10694860, Roles of nuclear architecture and phase separation in heterochromatin repair dynamics (5R01GM117376-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10694860. Licensed CC0.

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