DNA damage induces a kinetochore-based ATM/ATR-independent SAC arrest unique to the first meiotic division in mouse oocytes.
DNA damage induces a kinetochore-based ATM/ATR-independent SAC arrest unique to the first meiotic division in mouse oocytes.
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DOI：
10.1242/dev.153965
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发表时间：
2017-10-01
期刊：
影响因子：
--
通讯作者：
Jones KT
中科院分区：
文献类型：
--
作者：
Lane SIR;Morgan SL;Wu T;Collins JK;Merriman JA;ElInati E;Turner JM;Jones KT
携带DNA损伤的小鼠卵母细胞在减数分裂I中停止，从而阻止产生具有有害突变的胚胎。这种停滞依赖于纺锤体组装检查点的激活，从而导致后期促进复合体(APC)的抑制。然而，对于DNA损伤后这个检查站是如何进行的，人们知之甚少。在这里，我们发现，在dna损伤的几分钟内，检查点蛋白在着丝粒上组装，而不是在染色体臂上的损伤位置，因此在30 分钟内APC被完全抑制。尽管有这种强劲的反应，但K-纤维没有可测量的损失，或者二价纤维上的张力。通过药理抑制，我们观察到这种反应依赖于Mps1激酶、极光激酶和Haspin。使用卵母细胞特异的基因敲除，我们发现这种反应不需要DNA损伤反应，激酶，ATM或ATR。此外，在减数分裂II期间，检验点的激活不会对完全成熟的卵子中的DNA损伤做出反应，尽管分裂之间只有几个小时的距离。因此，小鼠卵母细胞有一种独特的能力，通过激活其运动中心的检查点来快速检测DNA损伤。MI卵母细胞的DNA损伤导致纺锤体组装检查点蛋白在动粒上的快速募集和激活，导致细胞周期停滞，从而阻止受损染色质的传播。
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. DNA damage in MI oocytes causes rapid recruitment and activation of spindle assembly checkpoint proteins at kinetochores leading to cell cycle arrest, thereby preventing the propagation of damaged chromatin.
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影响因子：
28.2
作者：
Bakhoum SF;Kabeche L;Murnane JP;Zaki BI;Compton DA
通讯作者：
Compton DA
DOI：
10.1038/nrm3494
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DNA损伤检查点的敏感性可防止子宫内膜异位症中的卵母细胞成熟。
影响因子：
4.6
作者：
Hamdan M;Jones KT;Cheong Y;Lane SI
通讯作者：
Lane SI
影响因子：
16
作者：
Callen, Elsa;Jankovic, Mila;Wong, Nancy;Zha, Shan;Chen, Hua-Tang;Difilippantonio, Simone;Di Virgilio, Michela;Heidkamp, Gordon;Alt, Frederick W.;Nussenzweig, Andre;Nussenzweig, Michel
通讯作者：
Nussenzweig, Michel
影响因子：
7.7
作者：
Heinrich, Stephanie;Sewart, Katharina;Hauf, Silke
通讯作者：
Hauf, Silke