Choreography of eukaryotic chromosome replication

人体包含超过一万亿个不同的细胞，每个细胞都是由细胞分裂产生的，这些细胞有效地相互作用，形成人体的组织和器官。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，而更简单的生命形式，如细菌和酵母，则由单个细胞组成。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进行自我复制以产生更多的细胞。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（例如脑细胞、血细胞或酵母细胞）的蓝图。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，每次DNA复制都是正确的，因为错误（突变）会改变细胞的特性，使细胞行为失常，例如在癌症中，或导致细胞（和生物体）死亡。许多机器相互作用来复制DNA，这种相互作用需要被仔细地控制和协调，以便DNA被正确地复制。复制DNA的机器可能类似于汽车的多个部件，如发动机、齿轮、离合器、制动器、加速器和方向盘。在汽车中，所有这些复杂的子部件相互作用和协调，使汽车按要求行驶。如果汽车的个别零件失灵，或协调失灵（例如离合器和油门之间），汽车很可能无法工作。人类基因组有30亿个碱基对，人体中的每个细胞都包含这么多碱基对。在复制30亿个碱基中的任何一个碱基时，一个错误都有可能是有害的，如果一个错误导致癌症，可能是最容易识别的。然而，考虑到复制整个细胞DNA内容的任务的重要性，不可避免地会出现错误。因此，为了帮助以最高的保真度复制DNA，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时减慢、停止或反向复制。我们用简单的酵母细胞，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几千年来用来制作面包、葡萄酒和啤酒的酵母细胞。我们对这些细胞进行了改造，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，或者可以通过抗生素或抗真菌药等药物在自然界中诱导。我们对DNA复制有缺陷的酵母细胞进行的实验使我们能够确定帮助细胞应对DNA复制失败的机制。我们发现了一些有趣的相互作用，让我们深入了解复制机制是如何被调节的。我们现在将使用强大的分子和细胞生物学方法来理解我们已经确定的相互作用的分子和生化基础。

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.