DNA damage responses in mammalian oocytes

Abstract

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...

True Nondisjunction of Whole Bivalents in Oocytes with Attachment and Congression Defects

“…Despite the fact that we can explain the increase of aneuploidy coincidently with maternal age by deterioration of cohesion between sister chromatids [Chiang et al, 2010;Lister et al, 2010] due to the absence of turnover of the cohesin complex during a prolonged prophase arrest [Revenkova et al, 2010;Tachibana-Konwalski et al, 2010], we are still uncertain why the aneuploidy is so high even in oocytes from young individuals in comparison to meiosis in yeast and Drosophila [Hassold and Hunt, 2001]. One of the mechanism, which likely contributes to this higher aneuploidy rate, is the spindle assembly checkpoint (SAC) and specifically changes to its function in oocytes compared to somatic cells [Mailhes, 2008;Jones and Lane, 2013;Touati and Wassmann, 2015;Collins and Jones, 2016].In a previous study, we demonstrated that the SAC in oocytes is unable to detect extensive chromosome alignment and congression defects by using animals generated by crossbreeding of 2 different mouse species, Mus mus- …”

The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis

“…The checkpoint that controls completion of oocyte maturation is the Spindle Assembly Checkpoint (SAC), named after its ability to prevent progression through the cell cycle until the spindle fully formed and chromosomes attached correctly in preparation for anaphase. We and others have recently shown an additional function of this checkpoint, unique to oocytes: its ability to prevent maturation in response to DNA damage10111213. As yet it is untested whether the extent of DNA damage required to activate the SAC-DDR checkpoint can occur pathologically or even physiologically.…”

Human oocytes harbouring damaged dna can complete meiosis-i

“…Recently, however, it was shown that DNA damage, which does not typically activate SAC in other cell types, apparently does so in mouse oocytes, suggesting the checkpoint has been adapted in female germ-cells to prevent DNA damage rather than aneuploidy (Collins and Jones, 2016). Our main finding here is that the same principle does not appear to apply in human oocytes.…”

“…In mouse oocytes the SAC can be activated and polar body extrusion prevented by two types of specific intervention; either by DNA damaging agents (Collins and Jones, 2016), or by extreme spindle disruption (Collins and Jones, 2016;Duncan et al, 2009). Our data demonstrates that DNA damage does not robustly activate SAC.…”

“…Recent experiments examining the impact of experimentally-induced DNA damage upon oocyte maturation led to an unexpected possible explanation for the aforementioned SAC failures in mouse. Multiple groups showed that oocytes harbouring DNA damage readily undergo Germinal Vesicle Breakdown but then arrest in meiosis-I harbouring an apparently normal MI (meiosis I) spindle, thereby failing to extrude the first polar body (Collins and Jones, 2016;Collins et al, 2015;Lane et al, 2017;Marangos and Carroll, 2012;Marangos et al, 2015). These results were unexpected since DNA damage in mammalian somatic cells tends to prevent nuclear envelope breakdown at mitosis entry (equivalent to preventing GVBD), but damage in mitosis does not prevent anaphase onset (Giunta et al, 2010;Rieder and Cole, 1998).…”