Pharmacological Inhibition of the DNA Damage Checkpoint Prevents Radiation-Induced Oocyte Death

Rinaldi, Vera D.; Hsieh, Kristin; Munroe, Robert J.; Bolcun-Filas, Eewlina M.; Schimenti, John C.

doi:10.1534/genetics.117.203455

Cited by 49 publications

(41 citation statements)

References 21 publications

(34 reference statements)

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“…Embryonic and postpartum explanted ovaries were cultured under conditions as we previously detailed (Rinaldi et al , 2017). Ovaries were irradiated in a 137 cesium irradiator with a rotating turntable.…”

Section: Star Methodsmentioning

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: Star Methodsmentioning

confidence: 99%

The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

et al. 2017

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“…However, based on our results, we propose that apoptosis pathway inhibitors may be candidate gonadoprotective agents against the toxic effects of CPA. We showed that two inhibitors, ETP-46464, a highly potent ATR-specific inhibitor (Forero et al 2014, Beumer et al 2015, and CHK2 inhibitors (CK2II), a Checkpoint 2 inhibitor (Coutandin et al 2016, Rinaldi et al 2017, Tuppi et al 2018, efficiently protected primordial follicles from 4-HC-induced damage in ovary organ culture in vitro. These findings further support a model in which CPA destroys primordial follicles through apoptotic pathways, and provides a rationale for further study of these agents in vivo.…”

Section: Figurementioning

confidence: 99%

Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide

Luan¹,

Edmonds²,

Woodruff

et al. 2019

Journal of Endocrinology

104

102

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Cancer therapy can cause off-target effects including ovarian damage, which may result in primary ovarian insufficiency in girls and premenopausal women. Loss of ovarian follicles within the ovarian reserve leads to ovarian endocrine dysfunction and impaired fertility. Cyclophosphamide (CPA), a commonly used chemotherapeutic and immunosuppressant agent, is a gonadotoxic agent that destroys ovarian cells by crosslinking DNA. To protect the ovary against CPA damage, we sought to precisely map the mechanism by which the ovarian reserve is depleted by CPA. We found that CPA specifically depletes primordial follicles without affecting primary and secondary follicles in three independent murine strains (CD-1, C57BL/6J and BALB/cJ) in vivo. We directly tested the effect of the active metabolite of CPA, 1 μM 4-hydroxyperoxycyclophophamide (4-HC), in vitro and confirmed the loss of primordial oocytes but no change in the number of primary and secondary follicles. We demonstrated that phospho-AKT (p-AKT) and cleaved PARP (cPARP) are present in primordial oocytes 3 days after CPA injection, consistent with the role of these markers as part of the apoptotic cascade. Interestingly, p-AKT positive primordial oocytes co-expressed cPARP. Treatment of animals with specific inhibitors of apoptotic pathway components, ETP46464 and CHK2, blocked 4-HC‒induced DNA damage in vitro. These data suggest that CPA targets primordial germ cells in the ovarian reserve by stimulating apoptosis pathways. Adjuvant therapies to protect primordial germ cells from the off-target effects of CPA may reduce the risk of POI.

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“…3B; Hayashi et al 2005). The post-birth oocyte loss is likely mediated by mechanisms that detect oocytes in which DSB repair and/or homolog synapsis were aberrant (Di Giacomo et al 2005;Kogo et al 2012;Wojtasz et al 2012;Bolcun-Filas et al 2014;Cloutier et al 2015;Rinaldi et al 2017;Qiao et al 2018). Both B6 tm/tm (Hayashi et al 2005;Diagouraga et al 2018) and PWD tm/tm adult females had small ovaries ( Fig.…”

Section: Prdm9 Is Important For Meiotic Synapsis In Pwd Males and Femmentioning

confidence: 99%

Histone methyltransferase PRDM9 is not essential for meiosis in male mice

et al. 2019

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A hallmark of meiosis is the rearrangement of parental alleles to ensure genetic diversity in the gametes. These chromosome rearrangements are mediated by the repair of programmed DNA double-strand breaks (DSBs) as genetic crossovers between parental homologs. In mice, humans, and many other mammals, meiotic DSBs occur primarily at hotspots, determined by sequence-specific binding of the PRDM9 protein. Without PRDM9, meiotic DSBs occur near gene promoters and other functional sites. Studies in a limited number of mouse strains showed that functional PRDM9 is required to complete meiosis, but despite its apparent importance, Prdm9 has been repeatedly lost across many animal lineages. Both the reason for mouse sterility in the absence of PRDM9 and the mechanism by which Prdm9 can be lost remain unclear. Here, we explore whether mice can tolerate the loss of Prdm9. By generating Prdm9 functional knockouts in an array of genetic backgrounds, we observe a wide range of fertility phenotypes and ultimately demonstrate that PRDM9 is not required for completion of male meiosis. Although DSBs still form at a common subset of functional sites in all mice lacking PRDM9, meiotic outcomes differ substantially. We speculate that DSBs at functional sites are difficult to repair as a crossover and that by increasing the efficiency of crossover formation at these sites, genetic modifiers of recombination rates can allow for meiotic progression. This model implies that species with a sufficiently high recombination rate may lose Prdm9 yet remain fertile.

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Pharmacological Inhibition of the DNA Damage Checkpoint Prevents Radiation-Induced Oocyte Death

Cited by 49 publications

References 21 publications

The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide

Histone methyltransferase PRDM9 is not essential for meiosis in male mice

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