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

View ORCID ProfileDaniel Wells, View ORCID ProfileEmmanuelle Bitoun, View ORCID ProfileDaniela Moralli, View ORCID ProfileGang Zhang, View ORCID ProfileAnjali Gupta Hinch, View ORCID ProfilePeter Donnelly, View ORCID ProfileCatherine Green, View ORCID ProfileSimon R Myers
doi: https://doi.org/10.1101/821678
Daniel Wells
The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UKDepartment of Statistics, University of Oxford, Oxford OX1 3LB, UK
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Emmanuelle Bitoun
The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UKDepartment of Statistics, University of Oxford, Oxford OX1 3LB, UK
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Daniela Moralli
The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK
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Gang Zhang
The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK
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Anjali Gupta Hinch
The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK
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Peter Donnelly
The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UKDepartment of Statistics, University of Oxford, Oxford OX1 3LB, UK
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Catherine Green
The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK
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Simon R Myers
The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UKDepartment of Statistics, University of Oxford, Oxford OX1 3LB, UK
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  • For correspondence: myers@stats.ox.ac.uk
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Abstract

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.

Graphical Abstract Legend In humans and other species, recombination is initiated by double strand breaks at sites bound by PRDM9. Upon binding, PRDM9 deposits the histone marks H3K4me3 and H3K36me, but the functional importance of these marks has remained unknown. Here, we show that PRDM9 recruits ZCWPW1, a reader of both these marks, to its binding sites genome-wide. ZCWPW1 does not help position the breaks themselves, but is essential for their downstream repair and chromosome pairing, and ultimately meiotic success and fertility in mice.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 30, 2019.
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ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair
Daniel Wells, Emmanuelle Bitoun, Daniela Moralli, Gang Zhang, Anjali Gupta Hinch, Peter Donnelly, Catherine Green, Simon R Myers
bioRxiv 821678; doi: https://doi.org/10.1101/821678
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ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair
Daniel Wells, Emmanuelle Bitoun, Daniela Moralli, Gang Zhang, Anjali Gupta Hinch, Peter Donnelly, Catherine Green, Simon R Myers
bioRxiv 821678; doi: https://doi.org/10.1101/821678

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