The Jackson Laboratory, Bar Harbor, ME 04609, United States of America.
PLoS Genet. 2018 Oct 26;14(10):e1007657. doi: 10.1371/journal.pgen.1007657. eCollection 2018 Oct.
In most mammals, including mice and humans, meiotic recombination is determined by the meiosis specific histone methytransferase PRDM9, which binds to specific DNA sequences and trimethylates histone 3 at lysine-4 and lysine-36 at the adjacent nucleosomes. These actions ensure successful DNA double strand break formation and repair that occur on the proteinaceous structure forming the chromosome axis. The process of hotspot association with the axis after their activation by PRDM9 is poorly understood. Previously, we and others have identified CXXC1, an ortholog of S. cerevisiae Spp1 in mammals, as a PRDM9 interactor. In yeast, Spp1 is a histone methyl reader that links H3K4me3 sites with the recombination machinery, promoting DSB formation. Here, we investigated whether CXXC1 has a similar function in mouse meiosis. We created two Cxxc1 conditional knockout mouse models to deplete CXXC1 generally in germ cells, and before the onset of meiosis. Surprisingly, male knockout mice were fertile, and the loss of CXXC1 in spermatocytes had no effect on PRDM9 hotspot trimethylation, double strand break formation or repair. Our results demonstrate that CXXC1 is not an essential link between PRDM9-activated recombination hotspot sites and DSB machinery and that the hotspot recognition pathway in mouse is independent of CXXC1.
在大多数哺乳动物中，包括小鼠和人类，减数分裂重组由减数分裂特异性组蛋白甲基转移酶 PRDM9 决定，它与特定的 DNA 序列结合，并在相邻核小体上的赖氨酸 4 和赖氨酸 36 处三甲基化组蛋白 3。这些作用确保了在形成染色体轴的蛋白质结构上发生成功的 DNA 双链断裂形成和修复。PRDM9 激活后热点与轴的关联过程尚不清楚。以前，我们和其他人已经确定 CXXC1 是哺乳动物中 S. cerevisiae Spp1 的同源物，作为 PRDM9 的相互作用物。在酵母中，Spp1 是一种组蛋白甲基阅读器，它将 H3K4me3 位点与重组机制联系起来，促进 DSB 的形成。在这里，我们研究了 CXXC1 是否在小鼠减数分裂中具有类似的功能。我们创建了两种 Cxxc1 条件性敲除小鼠模型，以普遍耗尽生殖细胞中的 CXXC1，并在减数分裂开始之前耗尽 CXXC1。令人惊讶的是，雄性敲除小鼠是可育的，而且精母细胞中 CXXC1 的缺失对 PRDM9 热点三甲基化、双链断裂形成或修复没有影响。我们的结果表明，CXXC1 不是 PRDM9 激活的重组热点与 DSB 机制之间的必要连接，并且小鼠中的热点识别途径独立于 CXXC1。
