Structural studies of protein-DNA complexes in recombination and repair

人类细胞的每一条染色体都有两个拷贝（一个是从父母那里遗传来的），它们携带着编码在DNA中的基因。因此，每个基因都有两个拷贝，一个来自父母，而等价的DNA分子对被称为？同源物？每个DNA分子都是一个双股螺旋结构。同源重组是一种自然机制，通过这种机制，细胞可以将DNA片段，从而将基因或基因的一部分，从一个DNA分子转移到另一个DNA分子上的等同位置。同源的？一个.这是一种机制，允许一个人从他/她的母亲那里继承一些特征，从他/她的父亲那里继承其他特征，因为它混合和匹配基因。因此，这是一个非常重要的进化过程。当两条染色体并排时，每条染色体上的一条DNA链断裂，然后连接到另一条染色体上相同位置的断裂DNA链上。交叉点，这是所谓的？霍利迪路口？能够在两条染色体之间上下滑动，一个分子中的少量或大量DNA可以从一条染色体转移到另一条染色体上。除了用于在染色体之间交换基因，并在儿童中产生明显的遗传特征混合物外，它还用于DNA修复的重要过程。我们的DNA不断受到损害，我们的每个细胞每天遭受数千次损伤，这种损害导致癌症等疾病。同源重组允许将等同的健康染色体DNA用作修复受损DNA的模板，如果没有这个系统，我们将无法长期生存。我们感兴趣的是，一旦染色体之间交换了足够多的DNA，细胞就会切断霍利迪连接，并允许两个DNA分子再次分离。细胞通常使用专门的蛋白质（酶）来切割霍利迪连接，我们之前已经研究了病毒中一个简单连接的结构。在这个项目中，我们将研究执行这项工作的几种人类酶的结构，以详细了解它们是如何工作的。遗传了这些酶的缺陷版本的人通常会患上癌症，对机制的充分理解应该有助于未来设计特定的治疗方法。

Human cells have two copies of each chromosome (one inherited from each parent) which carry their genes encoded in DNA. There are therefore two copies of each gene, one from each parent, and the equivalent pairs of DNA molecules are called ?homologues?. Each DNA molecule is a double helix with two strands. Homologous recombination is a natural mechanism, by which it is possible for the cell to move segments of DNA, and therefore genes or parts of genes, from one DNA molecule to the equivalent place on another ?homologous? one. This is the mechanism that allows a person to inherit some characteristics from his/her mother, and others from his/her father, as it mixes and matches the genes. It is therefore a very important evolutionary process. When two chromosomes are side by side, one strand of DNA on each chromosome is broken and then attached to a broken strand of DNA on the other chromosome at the equivalent position. The crossover point, which is called the ?Holliday junction?, is able to slide up and down between the two chromosomes, and a little or a lot of DNA from one molecule can be switched over from one to the other. As well as being used to exchange genes between chromosomes, and generate the obvious mixture of inherited characteristics in children, it is also used in the important process of DNA repair. Our DNA is constantly being damaged, each of our cells suffering thousands of lesions per day, and such damage leads to diseases such as cancer. Homologous recombination allows the equivalent healthy chromosome DNA to be used as a template to repair the damaged DNA, and without this system we would not survive for long. We are interested in the mechanism the cell uses to cut the Holliday junction once enough DNA has been exchanged between the chromosomes, and allow the two DNA molecules to separate again. Cells typically use specialised proteins (enzymes) to cut Holliday junctions and we have previously studied the structure of a simple one from a virus. In this project we will study the structure of several human enzymes that carry out this job to understand how they work in detail. People who inherit defective versions of these enzymes often develop cancers, and a full understanding of the mechanism should help the design of specific treatments in the future.