Structural studies of protein-DNA complexes in recombination and repair

人类细胞每条染色体都有两份拷贝(从父母各继承一份)，携带着DNA中编码的基因。因此，每个基因有两个拷贝，分别来自父母双方，相当的DNA分子对被称为同源基因。每个DNA分子都是由两条链组成的双螺旋结构。同源重组是一种自然的机制，通过这种机制，细胞可以将DNA片段，从而使基因或基因部分从一个DNA分子移动到另一个分子上的对等位置？一。这是一种机制，允许一个人在混合和匹配基因时，从他/她的母亲那里继承一些特征，从他/她的父亲那里继承另一些特征。因此，这是一个非常重要的演变过程。当两条染色体并排时，每条染色体上的一条DNA链被断裂，然后连接到另一条染色体上同等位置的一条断裂的DNA链上。交叉点被称为？Holliday连接，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可以从一个分子切换到另一个分子。除了被用来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，它还被用于DNA修复的重要过程。我们的DNA不断受到损伤，我们的每个细胞每天都会遭受数千次损伤，这种损伤会导致癌症等疾病。同源重组允许等同的健康染色体DNA被用作模板来修复受损的DNA，如果没有这个系统，我们将不会存活很长时间。我们感兴趣的是，一旦足够的DNA在染色体之间交换，细胞用来切断Holliday连接的机制，并允许两个DNA分子再次分离。细胞通常使用特殊的蛋白质(酶)来切断Holliday连接，我们之前已经研究了病毒的简单连接的结构。在这个项目中，我们将研究几种执行这项工作的人类酶的结构，以详细了解它们是如何工作的。遗传这些酶的缺陷版本的人往往会患上癌症，充分了解这种机制应该有助于未来设计具体的治疗方法。

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.