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Mol Cell. 2018 Mar 1;69(5):853-865.e6. doi: 10.1016/j.molcel.2018.01.033. Epub 2018 Feb 22.

PRDM9 Methyltransferase Activity Is Essential for Meiotic DNA Double-Strand Break Formation at Its Binding Sites.

Author information

1
IGH, CNRS, Université Montpellier, Montpellier, France.
2
Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5558, Villeurbanne, France.
3
Université Grenoble Alpes, CNRS, CEA, IBS, F-38000 Grenoble, France.
4
IGH, CNRS, Université Montpellier, Montpellier, France. Electronic address: bernard.de-massy@igh.cnrs.fr.
5
IGH, CNRS, Université Montpellier, Montpellier, France. Electronic address: frederic.baudat@igh.cnrs.fr.

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.

KEYWORDS:

DMC1; DNA double-strand break; H3K36me3; H3K4me3; PRDM9; chromatin; histone methylation; homologous recombination; meiosis; recombination hotspot

PMID:
29478809
DOI:
10.1016/j.molcel.2018.01.033
[Indexed for MEDLINE]
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