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Choreography of eukaryotic chromosome replication

真核染色体复制的编排

基本信息

批准号：
BB/M002314/1
负责人：
David Lydall
金额：
$ 43.94万
依托单位：
Newcastle University
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%2FM002314%2F1
关键词：
Choreography eukaryotic chromosome replication

项目摘要

The human body contains over a thousand billion different cells, each created by cell division, that productively interact to make the tissues and organs of the human body. All complex animals and plants are made of numbers of different cell types whereas simpler forms of life, such as bacteria and yeast, comprise single cells. All cell types including bacteria, yeast and human cells use the same basic mechanisms to replicate themselves to generate more cells. Perhaps the most important component of each cell is its DNA, which contains the blueprint to make the cell (for example a brain cell, blood cell, or yeast cell). For this reason, the mechanisms used to replicate cellular DNA are among the most important aspects of cell biology. It is important that DNA is replicated properly each time because mistakes (mutations) can change the properties of the cell making the cell misbehave, for example in cancer, or cause the cell (and organism) to die. Many machines interact to replicate DNA and the interactions need to be carefully controlled and coordinated in order that DNA is replicated properly. The machines that replicate DNA are perhaps analogous to those that individual multi-component parts of a car, such as engine, gears, clutch, brake, accelerator and steering wheel. In a car all these complex sub-components interact and coordinate to make the car drive as required. If individual parts of a car fail, or coordination fails (for example between clutch and accelerator) the car will most likely not work. The human genome is 3 billion base pairs and each cell in the body contains this number of bases. A single mistake in copying any of the three billion bases has the potential to be harmful, perhaps most recognisably if the single mistake contributes to causing cancer. However, given the magnitude of the task of replicating the entire cellular DNA content, it is inevitable that mistakes are made. Therefore to help replicate DNA with highest fidelity possible cells have evolved numerous mechanisms to check for errors. When errors are detected a number of mechanisms can slow, stop or reverse replication while errors are corrected. We have used simple yeast cells, a powerful model genetic system, to investigate how DNA replication is coordinated. These yeast cells are also the type that mankind has cultivated for thousands of years to make bread, wine and beer. We have engineered these cells and reduced the ability of the cells to replicate their DNA and then screened to identify the pathways and processes that respond to these defects. It is likely that similar defects are important during human ageing processes or can be induced in nature by drugs such as antibiotics or antifungals.Our experiments on yeast cells with defective DNA replication have allowed us to identify mechanisms that help cells cope with failures in DNA replication. We identified a number of interesting interactions that give insight into how the machinery of replication is regulated. We will now use powerful molecular and cellular biology methods to understand the molecular and biochemical basis of interactions we have identified.

人体包含超过1000亿个不同的细胞，每个细胞都是由细胞分裂产生的，它们相互作用，产生人体的组织和器官。所有复杂的动物和植物都是由许多不同类型的细胞组成的，而简单的生命形式，如细菌和酵母，则由单细胞组成。包括细菌、酵母和人类细胞在内的所有细胞类型都使用相同的基本机制来复制自己以产生更多的细胞。也许每个细胞最重要的组成部分是它的DNA，它包含了制造细胞的蓝图（例如脑细胞，血细胞或酵母细胞）。因此，用于复制细胞DNA的机制是细胞生物学中最重要的方面之一。重要的是，DNA每次都能正确复制，因为错误（突变）会改变细胞的特性，使细胞行为不端，例如在癌症中，或导致细胞（和生物体）死亡。许多机器相互作用以复制DNA，需要仔细控制和协调这些相互作用，以便正确复制DNA。复制DNA的机器可能类似于那些独立的汽车多组件部件，如发动机，齿轮，离合器，刹车，加速器和方向盘。在汽车中，所有这些复杂的子组件相互作用和协调，使汽车按要求行驶。如果汽车的个别部件出现故障，或者协调失败（例如离合器和加速器之间），汽车很可能无法工作。人类基因组有30亿个碱基对，人体内的每个细胞都含有这个数量的碱基。复制30亿个碱基中的任何一个错误都有可能是有害的，也许最容易识别的是，如果这个错误导致癌症。然而，考虑到复制整个细胞DNA内容的任务的艰巨性，犯错误是不可避免的。因此，为了帮助以最高的保真度复制DNA，可能的细胞已经进化出许多机制来检查错误。当检测到错误时，许多机制可以在纠正错误的同时减慢、停止或逆转复制。我们使用简单的酵母细胞，一个强大的模型遗传系统，来研究DNA复制是如何协调的。这些酵母细胞也是人类培养了数千年来制造面包，葡萄酒和啤酒的类型。我们对这些细胞进行了工程改造，降低了细胞复制DNA的能力，然后进行筛选，以确定对这些缺陷做出反应的途径和过程。类似的缺陷很可能在人类衰老过程中很重要，或者可以在自然界中由抗生素或抗真菌药等药物诱导。我们对DNA复制缺陷的酵母细胞进行的实验使我们能够确定帮助细胞科普DNA复制失败的机制。我们确定了一些有趣的相互作用，使深入了解如何复制机制的监管。我们现在将使用强大的分子和细胞生物学方法来了解我们已经确定的相互作用的分子和生物化学基础。