MEI4: a central player in the regulation of meiotic DNA double strand break formation in the mouse

Kumar, Rajeev; Ghyselinck, Norbert B.; Ishiguro, Kei‐ichiro; Watanabe, Yoshinori; Kouznetsova, Anna; Höög, Christer; Strong, Edward; Schimenti, John C.; Daniel, Katrin; Tóth, Attila; Massy, Bernard de

doi:10.1242/jcs.165464

Cited by 70 publications

(98 citation statements)

References 83 publications

(93 reference statements)

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“…The budding yeast HORMA-domain protein Hop1 helps recruit Mei4, Rec114 and Mer2 to axes 18 and mouse HORMAD1 is required for normal appearance of MEI4 foci that are presumptive DSB-promoting recombinosomes 16 . If IHO1 mediates HORMAD1 function in DSB formation, then IHO1 loss should also affect MEI4 complex assembly.…”

Section: Resultsmentioning

confidence: 99%

“…There is functional interplay between the axis and MCD recombinosomes for which HORMA-domain proteins are important, particularly in budding yeast 18 and mice 16 , but to a lesser extent in fission yeast 9,44,45 . HORMA-domain proteins are needed for robust accumulation of MCD recombinosome components on chromatin and axes in mice (ref 16 and this study), and on axis-binding DNA regions in budding yeast 18 .…”

Section: Discussionmentioning

confidence: 99%

“…SC formation is proposed to inhibit HORMAD1 functions and promote the depletion of HORMAD1 from axes 5,12 . This is one likely, but not exclusive, mechanism by which SC formation may also downregulate DSB formation and enable progression of meiocytes beyond prophase once homologues are successfully paired 5,7,12,16 . In this model, SC formation limits DSB numbers by restricting DSB formation to unsynapsed axes, precisely where DSBs are still needed to promote homologue engagement and SC formation 5,7 .…”

Section: Introductionmentioning

confidence: 99%

“…Mouse MEI4 is indispensable for DSB formation, and it interacts with REC114 and forms foci along unsynapsed chromosome axes 23 . These foci are thought to represent DSB-promoting recombinosomes because focus formation along axes correlates with DSB formation 16,23 . HORMAD1 that is associated with unsynapsed axes appears to be important for the function of these recombinosomes, as HORMAD1 is needed for efficient DSB formation 12–14 and high MEI4 focus numbers 16 .…”

Section: Introductionmentioning

confidence: 99%

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Meiotic DNA break formation requires the unsynapsed chromosome axis-binding protein IHO1 (CCDC36) in mice

et al. 2016

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DNA double-strand breaks (DSBs) are induced by SPO11 during meiosis to initiate recombination-mediated pairing and synapsis of homologous chromosomes. Germline genome integrity requires spatiotemporal control of DSB formation, which involves the proteinaceous chromosome axis along the core of each meiotic chromosome. In particular, a component of unsynapsed axes, HORMAD1, promotes DSB formation in unsynapsed regions where DSB formation must occur to ensure completion of synapsis. Despite its importance, the underlying mechanism has remained elusive. We identify CCDC36 as a direct interactor of HORMAD1 (IHO1) that is essential for DSB formation. Underpinning this function, IHO1 and conserved SPO11-auxiliary proteins MEI4 and REC114 assemble chromatin-bound recombinosomes that are predicted activators of DSB formation. HORMAD1 is needed for robust recruitment of IHO1 to unsynapsed axes and efficient formation and/or stabilization of these recombinosomes. Thus we propose that HORMAD1-IHO1 interaction provides a mechanism for the selective promotion of DSB formation along unsynapsed chromosome axes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Meiotic DNA break formation requires the unsynapsed chromosome axis-binding protein IHO1 (CCDC36) in mice

et al. 2016

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“…It is interesting to note that PRDM9 peak density is not evenly distributed along mouse chromosomes, and it will be interesting to evaluate whether it is related to features of chromosome organization. Two proteins required for meiotic DSB formation in mice (MEI4 and IHO1) are also located on the chromosomes axis (Kumar et al 2010(Kumar et al , 2015Stanzione et al 2016) and may also be unevenly distributed along chromosomes.…”

Section: Dom2mentioning

confidence: 99%

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

et al. 2017

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In mouse and human meiosis, DNA double-strand breaks (DSBs) initiate homologous recombination and occur at specific sites called hotspots. The localization of these sites is determined by the sequence-specific DNA binding domain of the PRDM9 histone methyl transferase. Here, we performed an extensive analysis of PRDM9 binding in mouse spermatocytes. Unexpectedly, we identified a noncanonical recruitment of PRDM9 to sites that lack recombination activity and the PRDM9 binding consensus motif. These sites include gene promoters, where PRDM9 is recruited in a DSB-dependent manner. Another subset reveals DSB-independent interactions between PRDM9 and genomic sites, such as the binding sites for the insulator protein CTCF. We propose that these DSB-independent sites result from interactions between hotspot-bound PRDM9 and genomic sequences located on the chromosome axis.

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