Mechanisms of DNA damage and repair in mature oocytes.

成熟卵母细胞 DNA 损伤和修复的机制。

• 批准号: BB/L006006/1
• 负责人: Keith Jones
• 金额: $ 61.3万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL006006%2F1
• 关键词: Mechanisms; DNA; damage; repair; mature

In preliminary work conducted in the lab of the applicant, a novel form of egg arrest has been observed in response to DNA damage. When immature oocytes are collected from the ovary they can undergo full maturation to become a fertilizable egg. However, if DNA damage is induced in the oocyte then often full maturation is inhibited, and instead the oocyte arrests at metaphase of the first meiotic division. The meiotic arrest is due to activation of the Spindle Assembly Checkpoint, a conserved cell cycle collection of proteins that are capable of arresting cells at metaphase, by persistent inhibition of the Anaphase Promoting Complex. Anaphase-onset is induced by Anaphase-Promoting Complex activity, and this is essential for exit from M-phase into G1 of the cell cycle. What appears important in oocytes is that DNA damage can induce activation of the Spindle Assembly Checkpoint. In all other cells examined DNA damage normally switches on a checkpoint that arrest cells at a different cell cycle phase- G2 (ie not the Spindle Assembly Checkpoint). Therefore usually the DNA damage checkpoint and the Spindle Assembly Checkpoint are considered separate pathways that operate at distinctly separate phases of the cell cycle. In oocytes the two checkpoints appear linked and is thought to be physiologically relevant because it would act to block the formation of mature eggs that would otherwise go onto to be fertilized and produce embryos with damaged DNA. Key to their interaction appears to be an already well known cell protein fizzy-related-1 (FZR1), and so this work will investigate these two checkpoints interact and why FZR1 should be involved. Therefore the work in this proposal will help establish a connection between two important cell cycle checkpoints that hitherto were seen to be separate, and it will help establish the importance of this association within a physiological context.

在申请人实验室进行的初步工作中，已经观察到了一种新型的卵子停滞形式，以应对DNA损伤。当从卵巢中收集未成熟的卵母细胞时，它们可以完全成熟成为可肥料的卵。但是，如果在卵母细胞中诱导DNA损伤，则通常会抑制完全成熟，而是在第一个减数分裂分裂的中期停滞的卵母细胞逮捕。减数分裂骤停是由于主轴组件检查点的激活，这是一种能够在中期时持续抑制后期促进复合物的蛋白质的保守细胞周期收集。后期发作是由促进后期的复合活性诱导的，这对于从M期退出到细胞周期的G1至关重要。在卵母细胞中似乎很重要的是，DNA损伤可以诱导主轴组件检查点的激活。在所有其他检查DNA损伤的细胞中，通常会在一个检查点上切换，该检查点在不同的细胞周期阶段G2（即纺锤体组装检查点）中逮捕细胞。因此，通常，DNA损伤检查点和主轴组件检查点被认为是在细胞周期明显单独的阶段运行的单独途径。在卵母细胞中，这两个检查点似乎是链接的，并且被认为在生理上是相关的，因为它会阻止成熟的卵的形成，否则这些卵将被施肥并产生带有受损DNA的胚胎。它们相互作用的关键似乎是已经众所周知的细胞蛋白质相关1（FZR1），因此这项工作将研究这两个检查点相互作用，以及为什么应涉及FZR1。因此，本提案中的工作将有助于在两个重要的细胞周期检查点之间建立联系，迄今认为是分开的，它将有助于在生理环境中确定该关联的重要性。

项目成果

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

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。

• DOI: 10.1038/srep36994
• 发表时间: 2016-11-14
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Hamdan M;Jones KT;Cheong Y;Lane SI
• 通讯作者: Lane SI

Gene editing can generate fragile bivalents in mouse oocytes

基因编辑可以在小鼠卵母细胞中产生脆弱的二价体

• DOI: 10.1101/350272
• 发表时间: 2018
• 作者: Manil-Ségalen M

DNA damage induces a kinetochore-based ATM/ATR-independent SAC arrest unique to the first meiotic division in mouse oocytes.

• DOI: 10.1242/dev.153965
• 发表时间: 2017-10-01
• 期刊: Development (Cambridge, England)
• 作者: Lane SIR;Morgan SL;Wu T;Collins JK;Merriman JA;ElInati E;Turner JM;Jones KT
• 通讯作者: Jones KT

Spindle tubulin and MTOC asymmetries may explain meiotic drive in oocytes.

• DOI: 10.1038/s41467-018-05338-7
• 发表时间: 2018-07-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Wu T;Lane SIR;Morgan SL;Jones KT
• 通讯作者: Jones KT

Chromosome structural anomalies due to aberrant spindle forces exerted at gene editing sites in meiosis.

• DOI: 10.1083/jcb.201806072
• 发表时间: 2018-10-01
• 期刊: The Journal of cell biology
• 作者: Manil-Ségalen M;Łuksza M;Kanaan J;Marthiens V;Lane SIR;Jones KT;Terret ME;Basto R;Verlhac MH
• 通讯作者: Verlhac MH