IGH, CNRS, Université Montpellier, Montpellier, France.
Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5558, Villeurbanne, France.
Mol Cell. 2018 Mar 1;69(5):853-865.e6. doi: 10.1016/j.molcel.2018.01.033. Epub 2018 Feb 22.
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.
数百个 DNA 双链断裂 (DSB) 的程序性形成对于减数分裂和生育能力至关重要。在老鼠和人类中，这些断裂的位置是由减数分裂特异性蛋白 PRDM9 通过其锌指结构域的 DNA 结合特异性决定的。PRDM9 还具有甲基转移酶活性。在这里，我们表明这种活性对于 H3K4me3 和 H3K36me3 的沉积以及 PRDM9 结合位点处的 DSB 形成是必需的。通过分析表达两种具有不同 DNA 结合特异性的 PRDM9 变体的小鼠，我们表明每个变体独立于另一个变体产生自己的 H3K4me3 标记集。总之，我们揭示了 PRDM9 依赖性 DSB 位点确定的几个基本原则，其中通过 PRDM9 结合和随后的组蛋白甲基化指定了过量的位点，从中选择一部分用于 DSB 形成。
