Abstract
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.
Highlights
Meiotic recombination ensures production of fertile gametes with a correct haploid chromosome number and genetic diversity [1]
These sites are proposed to become associated with the chromosome axis with the participation of additional proteins and undergo double strand breaks, which are repaired by homologous recombination
Our data suggest that even though CXXC1 interacts with PRDM9 in male germ cells, it does not play a crucial role in mouse meiotic recombination
Summary
Meiotic recombination ensures production of fertile gametes with a correct haploid chromosome number and genetic diversity [1]. The meiotic recombination sites are restricted to 1–2 kb regions, termed recombination hotspots, locations of which are determined by the DNA binding histone methyltransferase PRDM9 [2,3,4]. Recombination initiates when PRDM9 binds to hotspots sequences with its zinc finger domain and trimethylates histone 3 at lysine 4 (H3K4me3) and lysine 36 (H3K36me3) resulting in formation of a nucleosome-depleted region [2,3,4,5,6], probably by the action of nucleosome motors [7]. Efficient H3K4 trimethylation at hotspots is crucial for normal DSB formation and repair that occurs on the chromosome axis [17], even though PRDM9 binding presumably occurs on the open chromatin loops [18]. We currently do not have detailed knowledge of the proteins and molecular mechanisms participating in hotspot association with the chromosome axis
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