# Genetic regulation of genome stability in yeast

> **NIH NIH R35** · DUKE UNIVERSITY · 2024 · $706,866

## Abstract

Abstract
 Multiple genetic changes are necessary to convert a normal cell into a cancer cell. With a few
exceptions, the mutations or conditions (for example, DNA replication stress) that initiate genetic instability and
tumor formation are not understood. The goal of the proposed research is to use the yeast Saccharomyces
cerevisiae as a model for investigating the mechanisms that generate the various types of genetic instability
related to carcinogenesis. As an example of the success of this approach, our demonstration that DNA
mismatch repair mutations in yeast produced the same rate of microsatellite instability observed in hereditary
colorectal cancer cells was an important clue as to the causal mutation. 1. One of the proposed studies is the
characterization of a novel mutator that is responsive to base composition. We showed that a gene with high
GC content had a much-elevated mutation rate than genes with lower GC contents. We subsequently identified
a mutation (met18) that elevated the mutation rate of a high-GC gene more than 100-fold, with a much smaller
effect on other genes. The Met18 protein is a chaperone involved in the transport of Fe-S clusters into a variety
of enzymes involved in DNA replication and DNA repair. Our current data suggest that DNA polymerase delta
lacking the Fe-S cluster has substantially reduced processivity, accounting for the mutator phenotype of met18.
This hypothesis will be tested by our proposed experiments. 2. Fusions between centromeres are commonly
observed in tumor cells. We have developed a genetic system that allows the identification of recombination
events occurring between the centromeres of different yeast chromosomes. We will use this system to
examine the genetic regulation of centromere-centromere recombination. 3. We have recently used the
mammalian APOBEC protein, which deaminates cytosine in single-stranded DNA, to map regions of single-
stranded DNA in yeast cells undergoing DNA replication stress. Using APOBEC-induced mutations, we
propose extending our studies to map deletions and duplications in arrays of tandemly-repeated genes. Such
alterations are an important cause of genome instability. 4. Lastly, the Tel1p and Mec1p yeast proteins are
related functionally to the human ATM and ATR proteins, respectively. Mutations in both human genes are
associated with certain classes of tumors. Yeast cells with tel1 mec1 mutations have greatly elevated rates of
chromosome rearrangements and chromosome non-disjunction. The chromosome rearrangements, but not the
aneuploidy, are a consequence of a high rate of telomere fusions. We are testing the hypothesis that the high
level of chromosome non-disjunction is a consequence of defective phosphorylation of histone H2A in tel1
mec1 strains.

## Key facts

- **NIH application ID:** 10862689
- **Project number:** 5R35GM118020-09
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** THOMAS PETES
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $706,866
- **Award type:** 5
- **Project period:** 2016-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862689

## Citation

> US National Institutes of Health, RePORTER application 10862689, Genetic regulation of genome stability in yeast (5R35GM118020-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10862689. Licensed CC0.

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