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

Stanzione, Marcello; Baumann, Marek; Papanikos, Frantzeskos; Dereli, Ihsan; Lange, Julian; Ramlal, Angelique; Tränkner, Daniel; Shibuya, Hiroki; Massy, Bernard de; Watanabe, Yoshinori; Jasin, Maria; Keeney, Scott; Tóth, Attila

doi:10.1038/ncb3417

Cited by 155 publications

(341 citation statements)

References 63 publications

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“…Absence of the budding yeast ortholog Hop1p not only decreases meiotic DSB formation, but also increases use of the sister chromatid as a template for HR repair (Carballo et al , 2008; Lam and Keeney, 2014; Latypov et al , 2010; Mao-Draayer et al , 1996; Niu et al , 2005; Schwacha and Kleckner, 1997). Mouse HORMAD1 is required for loading HORMAD2 onto unsynapsed axes, proper SC formation (Daniel et al , 2011), and normal levels of meiotic DSBs (Daniel et al , 2011; Stanzione et al , 2016). Whereas Dmc1 −/− Hormad1 −/− or irradiated Hormad1 −/− oocytes exhibit fewer DSB markers than oocytes containing HORMAD1 (Daniel et al , 2011; Shin et al , 2010), this can be attributable largely to enhanced repair (Shin et al , 2013).…”

Section: Resultsmentioning

confidence: 99%

The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

et al. 2017

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SUMMARY Pairing and synapsis of homologous chromosomes during meiosis is crucial for producing genetically normal gametes, and is dependent upon repair of SPO11-induced double stranded breaks (DSBs) by homologous recombination. To prevent transmission of genetic defects, diverse organisms have evolved mechanisms to eliminate meiocytes containing unrepaired DSBs or unsynapsed chromosomes. Here, we show that the CHK2 (CHEK2)-dependent DNA damage checkpoint culls not only recombination-defective mouse oocytes, but also SPO11-deficient oocytes that are severely defective in homolog synapsis. The checkpoint is triggered in those oocytes that accumulate a threshold level spontaneous DSBs (~10) in late Prophase I, the repair of which is inhibited by presence of HORMAD1/2 on unsynapsed chromosome axes. Furthermore, Hormad2 deletion rescued fertility of oocytes containing a synapsis-proficient, DSB repair-defective mutation in a gene (Trip13) required for removal of HORMADs from synapsed chromosomes, suggesting that many meiotic DSBs are normally repaired by intersister recombination in mice.

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Section: Resultsmentioning

confidence: 99%

The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

et al. 2017

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“…Late in meiotic prophase, TRIP13 (Pch2 in S. cerevisiae and plants) mediates the removal of HORMADs from the chromosome axis (Borner et al , ; Joshi et al , ; Wojtasz et al , ; Lambing et al , ; Vader, ). This TRIP13‐mediated axis remodeling likely forms the basis of a feedback pathway that regulates recombination and ensures the fidelity of homolog pairing during meiosis (Wojtasz et al , , ; Daniel et al , ; Keeney et al , ; Thacker et al , ; Stanzione et al , ). Given the structural similarities between meiotic HORMADs and MAD2, it is likely that TRIP13 uses a common physical mechanism on both substrates and directly disassembles meiotic HORMAD complexes, but thus far this idea has not been directly tested.…”

Section: Introductionmentioning

confidence: 99%

The AAA + ATP ase TRIP 13 remodels HORMA domains through N‐terminal engagement and unfolding

Kim

Dereli

et al. 2017

The EMBO Journal

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Proteins of the conserved HORMA domain family, including the spindle assembly checkpoint protein MAD2 and the meiotic HORMADs, assemble into signaling complexes by binding short peptides termed "closure motifs". The AAA+ ATPase TRIP13 regulates both MAD2 and meiotic HORMADs by disassembling these HORMA domain-closure motif complexes, but its mechanisms of substrate recognition and remodeling are unknown. Here, we combine X-ray crystallography and crosslinking mass spectrometry to outline how TRIP13 recognizes MAD2 with the help of the adapter protein p31 We show that p31 binding to the TRIP13 N-terminal domain positions the disordered MAD2 N-terminus for engagement by the TRIP13 "pore loops", which then unfold MAD2 in the presence of ATP N-terminal truncation of MAD2 renders it refractory to TRIP13 action , and in cells causes spindle assembly checkpoint defects consistent with loss of TRIP13 function. Similar truncation of HORMAD1 in mouse spermatocytes compromises its TRIP13-mediated removal from meiotic chromosomes, highlighting a conserved mechanism for recognition and disassembly of HORMA domain-closure motif complexes by TRIP13.

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

Cited by 155 publications

References 63 publications

The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

The AAA + ATP ase TRIP 13 remodels HORMA domains through N‐terminal engagement and unfolding

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

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