RESEARCH ARTICLE ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair Daniel Wells1,2†*, Emmanuelle Bitoun1,2†*, Daniela Moralli1, Gang Zhang1, Anjali Hinch1, Julia Jankowska1, Peter Donnelly1,2, Catherine Green1, Simon R Myers1,2* 1The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United Kingdom; 2Department of Statistics, University of Oxford, Oxford, United Kingdom Abstract During meiosis, homologous chromosomes pair and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, double-strand breaks (DSBs) initiate recombination within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have been identified. We identified Zcwpw1, containing H3K4me3 and H3K36me3 recognition domains, as having highly correlated expression 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 recognises CpG dinucleotides. Male Zcwpw1 knockout mice show completely normal DSB positioning, but persistent DMC1 foci, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest ZCWPW1 recognition of PRDM9-bound sites at DSB hotspots is critical for *For correspondence: synapsis, and hence fertility.
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[email protected] (SRM) †These authors contributed Introduction equally to this work Meiosis is a specialised cell division, producing haploid gametes essential for reproduction. Uniquely, during this process homologous maternal and paternal chromosomes pair and exchange Competing interests: The DNA (recombine) before undergoing balanced independent segregation.