Abstract
Mouse oocytes carrying DNA damage arrest in meiosis I, thereby preventing creation of embryos with deleterious mutations. The arrest is dependent on activation of the spindle assembly checkpoint, which results in anaphase-promoting complex (APC) inhibition. However, little is understood about how this checkpoint is engaged following DNA damage. Here, we find that within minutes of DNA damage checkpoint proteins are assembled at the kinetochore, not at damage sites along chromosome arms, such that the APC is fully inhibited within 30 min. Despite this robust response, there is no measurable loss in k-fibres, or tension across the bivalent. Through pharmacological inhibition we observed that the response is dependent on Mps1 kinase, aurora kinase and Haspin. Using oocyte-specific knockouts we find the response does not require the DNA damage response kinases ATM or ATR. Furthermore, checkpoint activation does not occur in response to DNA damage in fully mature eggs during meiosis II, despite the divisions being separated by just a few hours. Therefore, mouse oocytes have a unique ability to sense DNA damage rapidly by activating the checkpoint at their kinetochores.
Highlights
The spindle assembly checkpoint (SAC) plays an essential role in reducing chromosome segregation errors by coupling anaphaseonset with biorientation, a state in which sister kinetochores are attached to microtubules emanating from opposite spindle poles (Foley and Kapoor, 2013; Lara-Gonzalez et al, 2012)
Inhibition of anaphase promoting complex (APC) activity associated with DNA damage in oocytes DNA damage that occurs in fully grown germinal vesicle-stage oocytes immediately prior to nuclear envelope breakdown (NEB) causes an arrest several hours later that is dependent on the SAC (Collins et al, 2015; Marangos et al, 2015)
We wanted to examine this association of DNA damage with SAC activation in more detail, and this was done by inducing DNA damage after NEB
Summary
The spindle assembly checkpoint (SAC) plays an essential role in reducing chromosome segregation errors by coupling anaphaseonset with biorientation, a state in which sister kinetochores are attached to microtubules emanating from opposite spindle poles (Foley and Kapoor, 2013; Lara-Gonzalez et al, 2012). Activated Mad is released into the cytoplasm to form part of. Mad along with Mad is displaced from kinetochores This leads to APC activation, through loss of the MCC, and so B-type cyclin and securin (Pttg1) degradation; these events are essential for mitotic exit (Foley and Kapoor, 2013; Lara-Gonzalez et al, 2012)
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