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ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

By Daniel Wells, Emmanuelle Bitoun, Daniela Moralli, Gang Zhang, Anjali Gupta Hinch, Peter Donnelly, Catherine Green, Simon Myers

Posted 30 Oct 2019
bioRxiv DOI: 10.1101/821678 (published DOI: 10.7554/eLife.53392)

During meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified. We identified Zcwpw1 , which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9 . Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognizes CpG dinucleotides, including within many Alu transposons. Male Zcwpw1 homozygous knockout mice show completely normal DSB positioning, but persistent DMC1 foci at many hotspots, particularly those more strongly bound by PRDM9, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest a model where ZCWPW1 recognition of PRDM9-bound sites on either the homologous, or broken, chromosome is critical for synapsis, and hence fertility.

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