# Chromosome structure, duplication and stability in yeast

> **NIH NIH R35** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $383,000

## Abstract

Project Summary/Abstract
Eukaryotic genome duplication requires that each chromosomal base pair is copied efficiently,
accurately and only once per cell division, a monumental demand given the millions to billions of
base pairs that comprise eukaryotic genomes and the countless cell divisions required to form
and sustain organisms. Severe defects in DNA replication are incompatible with life. However,
mild perturbations in this process, while still capable of supporting cell division, and which can
be challenging to identify using biochemical approaches, can compromise development and
health over the course of multiple cell divisions. Regulation of the first step, the initiation of DNA
replication that occurs at chromosomal positions called origins, is particularly critical in
eukaryotic cells because their chromosomes require multiple spatially and temporally distributed
origins for accurate and efficient duplication. Perturbations in origin number or distribution can
promote cancer, stem cell aging, or developmental disorders. While the origin-binding proteins
and molecular steps that define an origin are known, the mechanisms that regulate
chromosomal origin number and distribution are unclear. A challenge is that chromatin
heterogeneity exists across chromosomes as an intrinsic part of genome functional
organization. Thus, the origin-binding proteins must work sufficiently enough within distinct
chromatin environments to achieve a level of origin distribution that balances the competing
demands for cell proliferation and genome stability. Dr. Fox's lab addresses the gaps in
understanding how native chromatin structures regulate origin function by combining rigorous
genetics and genomics to reveal chromatin-mediated mechanisms that impinge on the structure
and function of Saccharomyces cerevisiae (yeast) origins. Emphasis is placed on the first step
of origin formation, the origin licensing reaction, which occurs in G1-phase of the cell cycle that
precedes the S-phase where origins perform their actual function, unwinding of the parental
DNA for new DNA synthesis. Accumulating evidence reveals that the licensing step is
particularly relevant to both genome stability and cell-fate decisions, but there is a paucity of
molecular mechanisms regarding how it is regulated in vivo to achieve chromosomal origin
distribution. Evolutionary conservation of the origin-binding proteins and multiple features of
chromatin allow the Fox laboratory to leverage the experimental strengths of yeast to define
fundamental mechanisms by which chromatin and the origin-binding proteins collaborate to form
and distribute origins over the genome.

## Key facts

- **NIH application ID:** 10202018
- **Project number:** 1R35GM141641-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Catherine A Fox
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,000
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202018

## Citation

> US National Institutes of Health, RePORTER application 10202018, Chromosome structure, duplication and stability in yeast (1R35GM141641-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10202018. Licensed CC0.

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