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Analysis of Xenopus Np95 during the cell cycle and in DNA damage responses

非洲爪蟾 Np95 在细胞周期和 DNA 损伤反应中的分析

基本信息

批准号：
BB/E015662/1
负责人：
Howard Lindsay
金额：
$ 40.23万
依托单位：
Lancaster University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FE015662%2F1
关键词：
Analysis Xenopus Np95 during cell

项目摘要

DNA is constantly subjected to damage caused by a wide variety of different factors. If this damage is left unrepaired then mutations can arise. If allowed to persist these mutations can lead to a loss of genome integrity. In order to protect the genome, cells have evolved mechanisms to prevent DNA damage or problems encountered during DNA replication from generating mutations. These mechanisms collectively known as DNA damage responses, detect damaged DNA or stalled DNA replication and can initiate a series of responses such as DNA repair, cell cycle arrest (allows time for repair), or if damage is too extensive, programmed cell death (apoptosis). Failure of DNA damage response pathways have been implicated in the development of cancer and in several human genetic diseases associated with a predisposition to cancer as well as developmental and neurological abnormalities. Understanding how these pathways operate and impinge on other cellular processes is therefore vital if human diseases such as cancer and many human developmental abnormalities are to be understood. Using cell-free extracts of amphibian eggs that recreate cell cycle events in the test tube we will study the role of a nuclear protein known as Np95. Np95 is upregulated in many types of cancer cell and cells lacking Np95 protein are highly sensitive to DNA damaging agents and drugs that inhibit DNA replication. These observations suggests that Np95 is also necessary for efficient DNA damage responses. We will use the Xenopus cell-free extract system to determine how and when Np95 function is required during the cell cycle and whether removing Np95 from egg extracts affects the cellular response to DNA damage.

DNA不断受到各种不同因素造成的损害。如果这种损伤没有得到修复，那么突变就会出现。如果允许这些突变持续存在，可能导致基因组完整性的丧失。为了保护基因组，细胞已经进化出防止DNA损伤或DNA复制过程中遇到的问题产生突变的机制。这些机制统称为DNA损伤反应，检测受损的DNA或停滞的DNA复制，并可以启动一系列反应，如DNA修复，细胞周期停滞（允许修复时间），或者如果损伤太大，程序性细胞死亡（凋亡）。DNA损伤反应途径的失败与癌症的发展和与癌症易感性相关的几种人类遗传疾病以及发育和神经异常有关。因此，如果要了解癌症和许多人类发育异常等人类疾病，了解这些途径如何运作并影响其他细胞过程至关重要。利用两栖动物卵的无细胞提取物在试管中重现细胞周期事件，我们将研究一种称为Np95的核蛋白的作用。Np95在许多类型的癌细胞中上调，并且缺乏Np95蛋白的细胞对DNA损伤剂和抑制DNA复制的药物高度敏感。这些观察结果表明，Np95也是有效的DNA损伤反应所必需的。我们将使用非洲爪蟾无细胞提取物系统，以确定如何以及何时Np95的功能是需要在细胞周期中，以及是否从鸡蛋提取物中去除Np95影响细胞对DNA损伤的反应。