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Updated: Feb 14, 2026
Live-Cell Imaging of Transcriptional Activity at DNA Double-Strand Breaks
Published on: September 20, 2021
PRDM9 Methyltransferase Activity Is Essential for Meiotic DNA Double-Strand Break Formation at Its Binding Sites
Boubou Diagouraga1, Julie A J Clément1, Laurent Duret2
1IGH, CNRS, Université Montpellier, Montpellier, France.
Abstract:
The programmed formation of hundreds of DNA double-strand breaks (DSBs) is essential for proper meiosis and fertility. In mice and humans, the location of these breaks is determined by the meiosis-specific protein PRDM9, through the DNA-binding specificity of its zinc-finger domain. PRDM9 also has methyltransferase activity. Here, we show that this activity is required for H3K4me3 and H3K36me3 deposition and for DSB formation at PRDM9-binding sites. By analyzing mice that express two PRDM9 variants with distinct DNA-binding specificities, we show that each variant generates its own set of H3K4me3 marks independently from the other variant. Altogether, we reveal several basic principles of PRDM9-dependent DSB site determination, in which an excess of sites are designated through PRDM9 binding and subsequent histone methylation, from which a subset is selected for DSB formation.
Insights
The protein PRDM9 guides DNA double-strand break (DSB) formation during meiosis. Its methyltransferase activity is crucial for histone modifications and DSB site selection, ensuring fertility.
Area of Science:
- Genetics
- Molecular Biology
- Reproductive Biology
Background:
- Meiosis requires programmed DNA double-strand breaks (DSBs) for genetic recombination and fertility.
- The protein PRDM9, through its zinc-finger domain, specifies the location of these DSBs in mammals.
- PRDM9 possesses both DNA-binding and methyltransferase activities.
Purpose of the Study:
- To investigate the role of PRDM9's methyltransferase activity in histone modification and DSB formation.
- To understand how distinct PRDM9 variants with different DNA-binding specificities influence DSB site determination.
Main Methods:
- Analysis of mice expressing different PRDM9 variants.
- Assessing histone modifications (H3K4me3, H3K36me3) at PRDM9-binding sites.
- Mapping of DSB locations in relation to PRDM9 binding and histone marks.
Main Results:
- PRDM9's methyltransferase activity is essential for H3K4me3 and H3K36me3 deposition at its binding sites.
- This activity is required for the formation of DSBs at these designated locations.
- Distinct PRDM9 variants independently establish their own H3K4me3 patterns.
- PRDM9 binding and histone methylation designate more potential DSB sites than are ultimately used.
Conclusions:
- PRDM9-dependent DSB formation involves an excess of designated sites, with a subset selected for breakage.
- Histone methylation, driven by PRDM9's methyltransferase activity, is a key mechanism in this selection process.
- These findings elucidate fundamental principles of PRDM9's role in regulating meiotic recombination and fertility.
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