ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/53392 |
| _version_ | 1811180970268688384 |
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| author | Daniel Wells Emmanuelle Bitoun Daniela Moralli Gang Zhang Anjali Hinch Julia Jankowska Peter Donnelly Catherine Green Simon R Myers |
| author_facet | Daniel Wells Emmanuelle Bitoun Daniela Moralli Gang Zhang Anjali Hinch Julia Jankowska Peter Donnelly Catherine Green Simon R Myers |
| author_sort | Daniel Wells |
| collection | DOAJ |
| description | 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 synapsis, and hence fertility. |
| first_indexed | 2024-04-11T09:12:08Z |
| format | Article |
| id | doaj.art-d1a82872483147549421c34c8c933946 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:12:08Z |
| publishDate | 2020-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d1a82872483147549421c34c8c9339462022-12-22T04:32:29ZengeLife Sciences Publications LtdeLife2050-084X2020-08-01910.7554/eLife.53392ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repairDaniel Wells0https://orcid.org/0000-0002-2007-8978Emmanuelle Bitoun1https://orcid.org/0000-0003-3439-2113Daniela Moralli2Gang Zhang3Anjali Hinch4Julia Jankowska5Peter Donnelly6Catherine Green7Simon R Myers8https://orcid.org/0000-0002-2585-9626The Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United Kingdom; Department of Statistics, University of Oxford, Oxford, United KingdomThe Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United Kingdom; Department of Statistics, University of Oxford, Oxford, United KingdomThe Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United KingdomThe Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United KingdomThe Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United KingdomThe Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United KingdomThe Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United Kingdom; Department of Statistics, University of Oxford, Oxford, United KingdomThe Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United KingdomThe Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United Kingdom; Department of Statistics, University of Oxford, Oxford, United KingdomDuring 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 synapsis, and hence fertility.https://elifesciences.org/articles/53392meiosisrecombinationdouble strand break repairZCWPW1PRDM9DMC1 |
| spellingShingle | Daniel Wells Emmanuelle Bitoun Daniela Moralli Gang Zhang Anjali Hinch Julia Jankowska Peter Donnelly Catherine Green Simon R Myers ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair eLife meiosis recombination double strand break repair ZCWPW1 PRDM9 DMC1 |
| title | ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair |
| title_full | ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair |
| title_fullStr | ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair |
| title_full_unstemmed | ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair |
| title_short | ZCWPW1 is recruited to recombination hotspots by PRDM9 and is essential for meiotic double strand break repair |
| title_sort | zcwpw1 is recruited to recombination hotspots by prdm9 and is essential for meiotic double strand break repair |
| topic | meiosis recombination double strand break repair ZCWPW1 PRDM9 DMC1 |
| url | https://elifesciences.org/articles/53392 |
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