p53 and TAp63 participate in the recombination-dependent pachytene arrest in mouse spermatocytes

Marcet-Ortega, Marina; Pacheco, Sarai; Martínez-Marchal, Ana; Castillo, Helena; Flores, Elsa R.; Jasin, Maria; Keeney, Scott; Roig, Ignasi

doi:10.1371/journal.pgen.1006845

Cited by 53 publications

(70 citation statements)

References 74 publications

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“…Altered DSB locations and formation of clustered DSBs may also contribute to asynapsis. Cells with synaptic defects die in pachytene from a recombination checkpoint, sex body failure, or both (Royo et al, 2010;Marcet-Ortega et al, 2017). We further surmise that some pachytene cells die from persistent DSBs (evidenced by γH2AX flares and recombination protein foci) even though they achieve full synapsis.…”

Section: Ankrd31 In Male and Female Fertilitymentioning

confidence: 65%

“…This result, along with elevated numbers of DMC1, RAD51, and RPA foci (Figures 3F-H), suggests that many cells contain a larger than usual number of incompletely repaired DSBs. Persistent DSBs at pachynema can trigger spermatocyte apoptosis (Pacheco et al, 2015;Marcet-Ortega et al, 2017), so this may account for some of the partially penetrant pachytene death in Ankrd31 -/mutants.…”

Section: Ankrd31 Deficiency Causes Dysregulated Recombinationmentioning

confidence: 99%

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REC114 partner ANKRD31 controls number, timing and location of meiotic DNA breaks

Boekhout

Karasu

Wang

et al. 2018

Preprint

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Double-strand breaks (DSBs) initiate the homologous recombination that is crucial for meiotic chromosome pairing and segregation.Here we unveil mouse ANKRD31 as a lynchpin governing multiple aspects of DSB formation. Spermatocytes lacking ANKRD31 have altered DSB locations and fail to target DSBs to sex chromosomes' pseudoautosomal regions (PAR). They also have delayed/fewer recombination sites but, paradoxically, more DSBs, suggesting DSB dysregulation. Unrepaired DSBs and pairing failures-stochastic on autosomes, nearly absolute on X and Y-cause meiotic arrest and sterility in males. Ankrd31-deficient females have reduced oocyte reserves. A crystal structure defines direct ANKRD31-REC114 molecular contacts and reveals a surprising pleckstrin homology domain in REC114. In vivo, ANKRD31 stabilizes REC114 association with the PAR and elsewhere. Our findings inform a model that ANKRD31 is a scaffold anchoring REC114 and other factors to specific genomic locations, promoting efficient and timely DSB formation but possibly also suppressing formation of clustered DSBs. We thank Attila Tóth and Bernard de Massy for discussions and sharing unpublished information. We thank Keeney lab members C. Claeys Bouuaert, N. Mohibullah, M. van Overbeek, and S. Kim for experimental advice. We thank MSKCC core facilities, supported by NIH cancer center core grant P30 CA008748: Mouse Genetics (P. Romanienko and W. Mark) for generating the Ankrd31 knockout; Molecular Cytology (K. Manova) for histology and expansion microscopy; the Integrated Genome Operation (A. Viale and N. Mohibullah) for sequencing; Bioinformatics (N. Socci) for analysis; and the Laboratory of Comparative Pathology (S. Monette) for necropsy. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). X-ray diffraction studies were

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Section: Ankrd31 In Male and Female Fertilitymentioning

confidence: 65%

Section: Ankrd31 Deficiency Causes Dysregulated Recombinationmentioning

confidence: 99%

REC114 partner ANKRD31 controls number, timing and location of meiotic DNA breaks

Boekhout

Karasu

Wang

et al. 2018

Preprint

Self Cite

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“…In addition, meiotic cells can be eliminated during prophase by a separate DNA damage checkpoint including ATM, CHK2 and the DNA damage response proteins p53 or p63 [17][18][19][20]23 . In line with the presence of such a checkpoint, we find a clear upregulation of TP63 (but not TP53) in human type I arrest spermatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Also in mouse oocytes, which do not contain a Y-chromosome or XY-silencing, the DNA damage checkpoint leads to specific activation of p63 20 . Moreover, it has been recently found that p53 and p63 are specifically involved in recombination-dependent mouse pachytene spermatocyte arrest 23 . We therefore propose that human type I spermatocyte elimination can be induced by a DNA damage signaling cascade that activates p63.…”

Section: Discussionmentioning

confidence: 99%

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Distinct prophase arrest mechanisms in human male meiosis

Jan

Jongejan

Korver

et al. 2017

Preprint

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To prevent chromosomal aberrations to be transmitted to the offspring, strict meiotic checkpoints are in place to remove aberrant spermatocytes. However, in about 1% of all males these checkpoints cause complete meiotic arrest leading to azoospermia and subsequent infertility. We here unravel two clearly distinct meiotic arrest mechanisms that act during the prophase of human male meiosis. Type I arrested spermatocytes display severe asynapsis of the homologous chromosomes, disturbed XY-body formation and increased expression of the Y-chromosome encoded gene ZFY and seem to activate a DNA damage pathway leading to induction of p63 mediated spermatocyte elimination. Type II arrested spermatocytes display normal chromosome synapsis, normal XY-body morphology and meiotic crossover formation but have a lowered expression of several cell cycle regulating genes and fail to properly silence the X-chromosome encoded gene ZFX. Discovery and understanding of these meiotic arrest mechanisms increases our knowledge on how genomic stability is guarded during human germ cell development.

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Central and Peripheral Expression of DNA Double‐Strand Breaks in Human and Mouse Tissues

Castiglione

Ramos

Leheste

et al. 2018

The Anatomical Record

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Mammalian cells accumulate DNA lesions when they undergo phases of the cell cycle or during normal cellular activity. In this regard, several DNA repair signaling pathways have evolved to maintain genome stability and avoid the potential acquisition of mutations. To define and further characterize the expression of DNA double-strand breaks in humans and mice, we used immunocytochemistry to localize a DNA damage signal within the spatial confines of the cell nucleus. We show that DNA double-strand breaks are abundantly expressed in postmitotic neurons of the human and mouse brain. Notably, DNA double-strand breaks are present in human hypothalamic and mouse striatal and hippocampal cells, with stable expression of the nuclear signal detected throughout the mammalian brain. Analysis of the mouse tongue, heart, and testis shows that expression of DNA double-strand breaks is only demonstrated in circumscribed populations of peripheral cells. These data suggest that levels of DNA double-strand breaks are tissue-specific with the tongue, heart and testicular tissue having different thresholds of DNA repair and DNA damage from those outlined at the brain level. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc.

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p53 and TAp63 participate in the recombination-dependent pachytene arrest in mouse spermatocytes

Cited by 53 publications

References 74 publications

REC114 partner ANKRD31 controls number, timing and location of meiotic DNA breaks

REC114 partner ANKRD31 controls number, timing and location of meiotic DNA breaks

Distinct prophase arrest mechanisms in human male meiosis

Central and Peripheral Expression of DNA Double‐Strand Breaks in Human and Mouse Tissues

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