# Mechanisms linking replication stress to genome instability in fission yeast

> **NIH NIH R35** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $707,322

## Abstract

Genome instability refers to changes in chromosome sequence, structure, or number that affect
normal cell function. Such instability is characteristic of cancer, as well as certain developmental and
neurological defects, and aging. Data from multiple organisms suggests that DNA replication stress is a
key contributor to genome instability. Mechanisms that stabilize replication forks, prevent abnormal
divisions, and promote DNA repair are a primary barrier to disease; therefore, understanding their
function and the consequences of their disruption has direct relevance to human health.
 This proposal employs an established model cell biology system, the fission yeast S. pombe,
to characterize how living cells respond to replication stress. S. pombe is a well-established genetic
model for chromosome biology that shares many features with human cells. Significantly, nearly all the
genes under study have orthologues in humans that have been associated with disease..
 A key aspect of the approach is to use live cell imaging to characterize the response to
replication stress and characterize its long term consequences. The overarching goal is to understand
the dynamics of replication stress and its resolution in normal and mutant cells. This includes
determining how the cell deploys molecular mechanisms to allow damage resolution and ensure
chromosome segregations. We address the cellular and genetic consequences of division under
stress; investigate how replication occurs late in G2 or mitosis to facilitate resolution; and examine the
three-dimensional organization of repair structures. We have previously shown that the pericentromere
is a fragile site, and we have expanded that to examine the ribosomal DNA and the role of phase
separation in contributing to gene integrity, as well as identification of other fragile regions. A novel
component is the analysis of replication stress during meiosis as a contributor to chromosome
rearrangements associated with birth defects and infertility.
 By combining this cell biological approach with superb yeast gene-discovery tools, and
identifying the molecular events that lead to abnormal divisions and further stress, this project tackles a
critical gap in current understanding. What are the pathways that contribute to different responses to
stress and their associated pathologies and how do they affect the biology of living cells? Together,
these studies provide a holistic picture of how conserved proteins interact to maintain genome stability
in a eukaryotic cell, identifying markers and risk factors for human disease.

## Key facts

- **NIH application ID:** 10404012
- **Project number:** 5R35GM118109-07
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** SUSAN L FORSBURG
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $707,322
- **Award type:** 5
- **Project period:** 2016-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404012

## Citation

> US National Institutes of Health, RePORTER application 10404012, Mechanisms linking replication stress to genome instability in fission yeast (5R35GM118109-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10404012. Licensed CC0.

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