DNA damage-induced metaphase I arrest is mediated by the spindle assembly checkpoint and maternal age

Marangos, Petros; Stevense, Michelle; Niaka, Konstantina; Lagoudaki, Michaela; Nabti, Ibtissem; Jessberger, Rolf; Carroll, John

doi:10.1038/ncomms9706

Cited by 124 publications

(140 citation statements)

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“…Having undergone GV breakdown, the oocyte then needs to progress through meiosis I, and arrest at metaphase of meiosis II, where it remains until fertilisation (Jones & Lane 2013). However, fully grown GV oocytes exposed to genotoxic agents such as NCS (Yuen et al 2012), etoposide (Collins et al 2015, Marangos et al 2015, UV-B and ionising radiation (Collins et al 2015) do not reach metaphase II and instead arrest in meiosis I (Fig. 1).…”

Section: An Oocyte-specific Dna Damage Checkpointmentioning

confidence: 99%

“…The block in meiosis I seen after most forms of DNA damage occurs before the metaphase to anaphase transition (Collins et al 2015, Marangos et al 2015. This transition is one of the major events in oocyte maturation, with bivalents reductionally segregating into sister chromatids.…”

Section: An Oocyte-specific Dna Damage Checkpointmentioning

confidence: 99%

“…The lack of response to interstrand crosslinks could allow this type of damage to be present in the mature oocyte. If left unrepaired, such genetic insults could lead to severe perturbations during embryonic development if fertilised.The block in meiosis I seen after most forms of DNA damage occurs before the metaphase to anaphase transition (Collins et al 2015, Marangos et al 2015. This transition is one of the major events in oocyte maturation, with bivalents reductionally segregating into sister chromatids.…”

mentioning

confidence: 99%

“…Several SAC components including MAD2, BUBR1 and MPS1 have all been shown to be heavily involved in this arrest (Collins et al 2015, Marangos et al 2015. Activation of the SAC after DNA damage does not appear to occur at the sites of DNA damage, instead evidence suggests that DNA damage is sensed at the kinetochore, where these proteins usually accumulate during canonical SAC signalling (Collins et al 2015, Marangos et al 2015. DNA damage caused by DSBs would have the potential to fragment DNA.…”

mentioning

confidence: 99%

“…Several SAC components, including MPS1 and MAD2, have been shown to be crucial for the DNA damage-induced metaphase arrest in oocytes (Collins et al 2015, Marangos et al 2015. Also, the MOS/ MAP kinase (MAPK) pathway, known to have a role in activating the meiotic SAC (Nabti et al 2014), appears to be integral for activating the DNA damage checkpoint in oocytes (Marangos et al 2015).Although ATM is involved in DNA damage-induced apoptosis in primordial follicles (Kim & Suh 2014), it appears not to contribute to SAC activation after DNA damage induction in fully grown GV oocytes, as pharmacological inhibition of the kinase does not rescue Figure 4 Relative sensitivity of the SAC to biorientation and DNA damage in oocytes. (A) Oocyte SAC response to non-attachment: during early prometaphase, there are several bivalents without correct microtubule attachment to the spindle.…”

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DNA damage responses in mammalian oocytes

Collins¹,

Jones²

2016

Reproduction

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DNA damage acquired during meiosis can lead to infertility and miscarriage. Hence, it should be important for an oocyte to be able to detect and respond to such events in order to make a healthy egg. Here, the strategies taken by oocytes during their stages of growth to respond to DNA damaging events are reviewed. In particular, recent evidence of a novel pathway in fully grown oocytes helps prevent the formation of mature eggs with DNA damage. It has been found that fully grown germinal vesicle stage oocytes that have been DNA damaged do not arrest at this point in meiosis, but instead undergo meiotic resumption and stall during the first meiotic division. The Spindle Assembly Checkpoint, which is a well-known mitotic pathway employed by somatic cells to monitor chromosome attachment to spindle microtubules, appears to be utilised by oocytes also to respond to DNA damage. As such maturing oocytes are arrested at metaphase I due to an active Spindle Assembly Checkpoint. This is surprising given this checkpoint has been previously studied in oocytes and considered to be weak and ineffectual because of its poor ability to be activated in response to microtubule attachment errors. Therefore, the involvement of the Spindle Assembly Checkpoint in DNA damage responses of mature oocytes during meiosis I uncovers a novel second function for this ubiquitous cellular checkpoint. Reproduction (2016) 152 R15-R22cryopreservation of embryos and oocytes (Maltaris et al. 2007, ASRM 2013, Roness et al. 2014, Skaznik-Wikiel et al. 2015. Unfortunately, these methods cannot be applied to all. One limitation of this technique is that a partner, or willingness to use a donor, is required to provide sperm. Hormonal suppression of ovaries during cancer treatment is another option for women; however, the use of such drugs has potential associated risks such as interference with the cancer treatment or survival of eggs with DNA damage (Roness et al. 2014).However, the major limitation of cryopreservation methods is that they can only be used in post-pubertal women. Therefore, there are currently no established options for young pre-pubertal girls (Skaznik-Wikiel et al. 2015). Experimental options include ovarian tissue cryopreservation, but this has a variety of risks associated with it (Maltaris et al. 2007, Skaznik-Wikiel et al. 2015.In this review, we will focus on the various strategies that oocytes elicit, in the adult, upon damage to their DNA. This includes the apoptosis of primordial follicles, evasion of the G2/M checkpoint and a metaphase arrest induced by DNA damage. Programmed doublestrand breaks (DSBs) occur in foetal life during meiotic recombination and pose a potential threat to oocytes if left unrepaired. However, only responses to exogenous sources of DNA damage will be discussed here. R16 J K Collins and K T JonesReproduction (2016) 152 R15-R22www.reproduction-online.org Primordial follicle apoptosis after DNA damageAt birth, the reserve of oocytes has been established and is held within primordial follicles ar...

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Section: An Oocyte-specific Dna Damage Checkpointmentioning

confidence: 99%

Section: An Oocyte-specific Dna Damage Checkpointmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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DNA damage responses in mammalian oocytes

Collins¹,

Jones²

2016

Reproduction

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Guardians of Oocyte Quality

Ruebel

Latham

2018

Encyclopedia of Life Sciences

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Oocyte quality is fundamental to assisted reproduction, agricultural livestock productivity and species preservation. Mammalian oocytes develop in close coordination with somatic follicle cells of the ovary, and manifest remarkable molecular mechanisms that serve as guardians of oocyte quality and integrity. Genome and mitochondrial integrity are major aspects of oocyte quality determination. Ongoing research is revealing the details of these mechanisms, and how they help protect oocytes from detrimental effects of exogenous factors. Key Concepts Oocyte quality is essential for assisted reproduction success. Development of the oocyte involves an intricate set of bidirectional signals between the oocyte, cumulus cells and follicular fluid components, which can impact the quality of the oocyte. Chromosome segregation and adaptability to DNA damage are critical for the integrity of oocyte's genome. Energy production, proper distribution of mitochondria and regulation of fusion/fission are essential for maintaining the integrity of the mitochondria and oocyte developmental competence. Overall, oocyte maturation and development is a highly regulated process, and disruption in this process could comprise the mitochondrial and genomic integrity, further impacting the health of the oocytes. There are a variety of extrinsic factors, such as maternal health, maternal diet and environmental exposures, that can further impact oocyte quality. Therapies such as antioxidant, melatonin, CoQ10 and resveratrol treatments have been suggested to improve oocyte quality, but more studies are needed to determine efficacy. Novel biomarkers of oocyte quality need to be discovered.

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Multi‐Omics Analysis Reveals Translational Landscapes and Regulations in Mouse and Human Oocyte Aging

Huang

Chen

et al. 2023

Advanced Science

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Abnormal resumption of meiosis and decreased oocyte quality are hallmarks of maternal aging. Transcriptional silencing makes translational control an urgent task during meiosis resumption in maternal aging. However, insights into aging‐related translational characteristics and underlying mechanisms are limited. Here, using multi‐omics analysis of oocytes, it is found that translatomics during aging is related to changes in the proteome and reveals decreased translational efficiency with aging phenotypes in mouse oocytes. Translational efficiency decrease is associated with the N6‐methyladenosine (m6A) modification of transcripts. It is further clarified that m6A reader YTHDF3 is significantly decreased in aged oocytes, inhibiting oocyte meiotic maturation. YTHDF3 intervention perturbs the translatome of oocytes and suppress the translational efficiency of aging‐associated maternal factors, such as Hells, to affect the oocyte maturation. Moreover, the translational landscape is profiled in human oocyte aging, and the similar translational changes of epigenetic modifications regulators between human and mice oocyte aging are observed. In particular, due to the translational silence of YTHDF3 in human oocytes, translation activity is not associated with m6A modification, but alternative splicing factor SRSF6. Together, the findings profile the specific translational landscapes during oocyte aging in mice and humans, and uncover non‐conservative regulators on translation control in meiosis resumption and maternal aging.

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DNA damage-induced metaphase I arrest is mediated by the spindle assembly checkpoint and maternal age

Cited by 124 publications

References 60 publications

DNA damage responses in mammalian oocytes

DNA damage responses in mammalian oocytes

Guardians of Oocyte Quality

Multi‐Omics Analysis Reveals Translational Landscapes and Regulations in Mouse and Human Oocyte Aging

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