PRDM9 Methyltransferase Activity Is Essential for Meiotic DNA Double-Strand Break Formation at Its Binding Sites
PRDM9 Methyltransferase Activity Is Essential for Meiotic DNA Double-Strand Break Formation at Its Binding Sites
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DOI：
10.1016/j.molcel.2018.01.033
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发表时间：
2018-03-01
期刊：
影响因子：
16
通讯作者：
Baudat, Frederic
中科院分区：
文献类型：
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作者：
Diagouraga, Boubou;Clement, Julie A. J.;Baudat, Frederic
数百个DNA双链断裂（DSB）的编程形成对于适当的减数分裂和生育至关重要。在小鼠和人类中，这些断裂的位置由减数分裂特异性蛋白PRDM9通过其锌指域的DNA结合特异性确定。 PRDM9还具有甲基转移酶活性。在这里，我们表明此活动是H3K4ME3和H3K36ME3沉积以及PRDM9结合位点的DSB形成所必需的。通过分析具有具有不同DNA结合特异性的两个PRDM9变体的小鼠，我们表明每个变体都会独立于其他变体生成自己的H3K4ME3标记。总的来说，我们揭示了依赖PRDM9的DSB位点测定的几个基本原理，其中通过PRDM9结合和随后的组蛋白甲基化指定了过多的位点，从中选择了DSB形成的子集。
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.