# Chromosomal control of meiotic double-strand break formation

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2020 · $306,623

## Abstract

Project Summary
The formation of gametes in most sexually reproducing organisms involves a stage of controlled genome
fragmentation and reshuffling known as meiotic recombination. Aside from promoting genetic diversity, the
exchange of DNA sequences serves to tether homologous chromosomes, which is essential for controlled
chromosome assortment into sperm or eggs. Meiotic recombination is initiated by the programmed induction of
hundreds of DNA double-strand breaks (DSBs), which occur preferentially in chromosomal hotspots. Recent
work has defined chromatin modifications that correlate with the positions of meiotic DSB hotspots. However,
those modifications are poor predictors of actual hotspot usage, indicating the existence of additional
determinants. The overall goal of this project is to define the molecular mechanisms governing meiotic hotspot
usage. Hotspot usage will be investigated in the sexually reproducing yeast Saccharomyces cerevisiae, which
has served as successful model for many aspects of meiotic recombination. Preliminary experiments in S.
cerevisiae identified a conserved chromatin regulator that, when mutated, dramatically alters relative hotspot
usage. The proposed experiments will determine the function of this regulator in controlling DSB levels, and
take advantage of the altered DSB landscape of this mutant to determine the features of chromatin architecture
and DNA topology that remain specifically associated with hot DSB hotspots. In addition, preliminary
experiments have identified a characterisitic DNA topology that appears to predict hotspot activity. The
proposed experiments will address if this DNA topology is related to supercoiling and will investigate the
function of several topology-sensitive enzymes in influencing the activity of meiotic DSB hotspots. The
proposed experiments will also use genome-wide methods to probe the three-dimensional conformation of
meiotic chromosomes and determine the effects on hotspot usage when these conformations are altered.
Together, the proposed experiments will provide a high-resolution view of meiotic chromosome structure and
define the role of this architecture in faithfully guiding the formation of hundreds of meiotic DSBs as a
prerequisite to productive gamete formation and fertility.

## Key facts

- **NIH application ID:** 9840911
- **Project number:** 5R01GM123035-03
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Andreas Hochwagen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,623
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840911

## Citation

> US National Institutes of Health, RePORTER application 9840911, Chromosomal control of meiotic double-strand break formation (5R01GM123035-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9840911. Licensed CC0.

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