# Supplement: 53BP1 regulates genome biology and cellular physiology through liquid phase separation

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $248,989

## Abstract

Humans inevitably age, and often develop cancer. A fundamental cause of aging and cancer is the loss of
genome stability (abnormalities in nuclear DNA or chromosomes). Hence, understanding mechanisms
regulating genome stability has huge impact on biology and human health. Hypothesis related to genomic
instability generation and cancer evolution has long been revolved around the DNA damage response and
repair programs that control DNA metabolism. Our recent findings indicate an important role of liquid phase
separation, an emerging biological process by which proteins and nucleic acids form membraneless liquid
droplets/condensates inside cells to respond to environmental and internal cues, in regulating genome stability.
We demonstrated that this activity preserves the structure and the function of heterochromatin through a
protein called 53BP1; importantly, this new protective activity of 53BP1 is independent of its widely known role
in DNA double strand break (DSB) repair (Nat Communications, 2022). Hence, our results open a new
research paradigm in studying genome stability regulation and stress response. The overarching goal of this
application is to establish this research paradigm by understanding the mechanism and the impact of 53BP1
liquid phase separation. Two Aims are proposed. Aim 1 will determine how exactly 53BP1 phase separates
at heterochromatin. Aim 2 will determine the biological significance of 53BP1 phase separation. By
assembling an interdisciplinary team consisting of experts on molecular and cellular biology, proteomics,
computational bioinformatics, and next generation sequencing, we will use a combination of cell biological,
molecular, biochemical, genetic, morphological, and chemical approaches to answer these questions. Upon
completion, our studies will illustrate a previously uncharacterized function of 53BP1 and a novel interplay
between 53BP1 and heterochromatin and determine their impact on genome stability, facilitating our
understanding of fundamental cellular information processing, cellular homeostasis, and cellular physiology. To
the best of my knowledge, no other investigators are working on this research direction.

## Key facts

- **NIH application ID:** 11035592
- **Project number:** 3R01GM148662-01S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** You-Wei Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,989
- **Award type:** 3
- **Project period:** 2023-09-04 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11035592

## Citation

> US National Institutes of Health, RePORTER application 11035592, Supplement: 53BP1 regulates genome biology and cellular physiology through liquid phase separation (3R01GM148662-01S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/11035592. Licensed CC0.

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