# Enzymatic Mechanisms of Genetic Recombination

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $463,607

## Abstract

PROJECT SUMMARY
 Gross chromosomal rearrangements (GCRs) are mutations that underlie many genetic diseases. Many
cancers have increased accumulation of GCRs, which likely represents a type of mutator phenotype thought to
be important for the development and progression of these cancers. Consistent with this, some inherited
cancer susceptibility syndromes result from genetic defects that cause increased accumulation of GCRs in
model systems. While many pathways thought to play a role in preventing GCRs have been studied, a
comprehensive understanding of the genes, pathways and mechanisms that prevent accumulation of GCRs is
not available. Understanding these mechanisms will impact on human health for several reasons: 1) Identifying
genes and mechanisms that suppress and promote GCRs will provide tools to identify causes of genome
instability in cancer; 2) The development of PARP inhibitors for treating cancers with BRCA1 and BRCA2
defects has demonstrated that defects causing genome instability are potential therapeutic targets for cancer;
and, 3) Understanding pathways that suppress accumulation of GCRs, including identifying synthetic lethal
partner genes for these pathways, will provide critical information for guiding developing of novel cancer
diagnostics and therapeutic approaches for use in personalized approaches to cancer treatment.
 The goal of this proposal is to use Saccharomyces cerevisiae to identify genes, pathways and
mechanisms that suppress GCRs that will then guide the development of assays for the formation of GCRs in
human cells. Key related objectives are to identify chromosomal features and aberrant DNA repair
mechanisms that contribute to the formation of GCRs and to identify human genes in which defects cause
genome instability in cancer. The proposed studies will build on the results of work supported by this project
that have resulted in a series of quantitative assays for use in studying GCRs and have identified numerous
genome instability suppressing (GIS) genes and cooperating GIS genes that suppress the accumulation of
GCRs in S. cerevisiae. The following lines of research will be carried out: 1) The mechanistic features of
selected pathways that suppress GCRs will be investigated, focusing on Tor2 (a tumor suppressor
homologue), the cohesion and condensin complexes, and Exonuclease 1; 2) Genetic studies and whole
genome sequencing will be used to identify the genes and mechanisms that suppress or promote GCRs
mediated by the formation of large loop ssDNA hairpin-mediated GCRs and study the genomic features that
underlie the formation of specific GCRs; 3) The mechanistic and genetic features of the formation of individual
GCRs will be studied using a newly developed assay that allows monitoring of the formation of an individual
GCR by PCR; and, 4) GCR assays for use in human cells will be developed and used to investigate defects in
human GIS genes. These studies will provide a comprehensive picture of the pathways a...

## Key facts

- **NIH application ID:** 10913290
- **Project number:** 5R01GM026017-47
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Richard D Kolodner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $463,607
- **Award type:** 5
- **Project period:** 1978-12-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913290

## Citation

> US National Institutes of Health, RePORTER application 10913290, Enzymatic Mechanisms of Genetic Recombination (5R01GM026017-47). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10913290. Licensed CC0.

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