Every day, thousands of DNA breaks occur inside each of our cells, and a set of human enzymes must snip and re-stitch these strands to prevent cancer. This project studies the molecular structure of those enzymes—specifically the ones that cut a DNA crossover point called the Holliday junction during homologous recombination. This process normally swaps genetic material between chromosomes and repairs damaged DNA. When the cutting step fails, cells accumulate dangerous mutations. People born with faulty versions of these enzymes are prone to developing cancers. Current knowledge of the cutting mechanism comes largely from a viral enzyme; the human versions are more complex and poorly understood. The research is fundamental science. It will produce detailed three-dimensional structures of human Holliday junction-resolving enzymes, revealing exactly how they recognise and cut DNA. There is no immediate clinical application. However, understanding these molecular mechanics could eventually guide the design of drugs that either block the repair process in cancer cells (making them vulnerable to chemotherapy) or restore it in cells where it is broken. Similar structural work on DNA-repair proteins has already informed the development of PARP inhibitors, now used to treat certain breast and ovarian cancers.
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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.
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