Mechanisms of DNA damage and repair in mature oocytes.

成熟卵母细胞 DNA 损伤和修复的机制。

基本信息

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

项目摘要

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，观察到一种针对 DNA 损伤的新型卵子停滞形式。当从卵巢收集未成熟的卵母细胞时，它们可以完全成熟，成为受精卵。然而，如果在卵母细胞中诱导DNA损伤，则通常会抑制完全成熟，并且卵母细胞在第一次减数分裂的中期停滞。减数分裂停滞是由于纺锤体组装检查点的激活所致，纺锤体组装检查点是一种保守的细胞周期蛋白质集合，能够通过持续抑制后期促进复合物将细胞停滞在中期。后期启动是由后期促进复合物活性诱导的，这对于细胞周期从 M 期进入 G1 期至关重要。对于卵母细胞来说，重要的是 DNA 损伤可以诱导纺锤体组装检查点的激活。在所有其他检查的细胞中，DNA 损伤通常会开启一个检查点，将细胞捕获在不同的细胞周期阶段 - G2（即不是纺锤体组装检查点）。因此，通常 DNA 损伤检查点和纺锤体组装检查点被认为是在细胞周期的明显不同阶段运行的独立途径。在卵母细胞中，这两个检查点似乎是相关的，并且被认为具有生理相关性，因为它会阻止成熟卵子的形成，否则成熟卵子会继续受精并产生DNA受损的胚胎。它们相互作用的关键似乎是众所周知的细胞蛋白 fizzy-relative-1 (FZR1)，因此这项工作将研究这两个检查点的相互作用以及为什么 FZR1 应该参与其中。因此，本提案中的工作将有助于在迄今为止被认为是独立的两个重要的细胞周期检查点之间建立联系，并将有助于确定这种联系在生理背景下的重要性。