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The process of DNA replication is complex, and mistakes can lead to genome instability. Surveillance systems are not always successful which results in mutations that have the potential to inactivate genes or change their activity. This can lead to cancer, and many chemotherapeutic drugs are designed to disrupt DNA replication. A better understanding of these mechanisms can help us develop new drugs with reduced side effects.

Q: Can you tell us what can go wrong when DNA is replicated?

Catherine Green: I guess we have all become familiar with the structure of the DNA helix, how two strands of DNA intertwine around each other in this twisted ladder structure with each strand being made up of the four bases: A, G, C and T. That structure leads to the mechanism by which DNA can be replicated or copied, the two strands can separate from each other and each strand can be used as a template for the synthesis of two identical strands. This process is essential in cells because cells are forever needing to copy themselves to produce daughter cell, to replenish cells which are lost during everyday life.

Q: What causes genome instability?

CG: Genome instability can arise during DNA replication in many different ways. The enzymes and the machinery that's used by cells to perform DNA replication to copy our DNA is not 100% accurate. Most of the time those mistakes made by the DNA replication machinery will be picked up and corrected before they become mutations. But even these surveillance processes are not 100% accurate. However, there are some lifestyle choices that we make that can increase the chance that DNA replication leads to genome instability. For example, when we go outside in the sunshine or lie on a sunbed, we expose the cells of our skin to ultraviolet radiation. Ultraviolet light is very harmful to the DNA in those cells because the energy of ultraviolet light is absorbed by DNA and causes a chemical change. Similar changes and similar genome instability can arise due to chemicals in tobacco smoke or in other environmental carcinogens.

Q: How can genome instability lead to the development of cancer?

CG: Some changes to our genome, some mutations, will have a very limited effect. DNA changes that change a single base in a region of the genome that's not being used, for example, might not have consequence at all to cells. But, sometimes a single base change in our genome can have a serious effect. For example, if that single base change inactivates a gene which is required for a surveillance pathway that prevents cancer, or a DNA repair mechanism that ensures that our genomes are ok and maintained healthily. Another way that genome instability can cause cancer is by causing genome rearrangements. During the process of DNA replication breaks may happen to the DNA and those breaks have to be joined back together again. But, if pieces of DNA which are in linear space are joined back together erroneously you can move around pieces of the genome relative to each other. Because our genome is made up of pieces of DNA which regulate other pieces of DNA such genome rearrangements can mean that genes, although they are still normal unmutated genes, are moved into parts of the genome where their regulation is perturbed. That can lead to perturbed cell functions which then can generate tumour regenesis.

Q. What are the most important lines of research that have developed in the past five or ten years?

CG: There have probably been three changes in our understanding of genomes and how genome instability contributes to cancer.
The first is the scale of genome instability that underpins cancer development. Recent developments in sequencing technologies mean that we can now analyse what's happened in cancer cells, compared to normal cells in the same individual. There are hundreds and thousands of changes in cancer cells relative to normal cells in our body. One of the big challenges now is to start to dissect out which of those changes are the causing changes, the mutations which have the consequences for the cell which result in cancer, and those which are just passengers, mutations which have arisen but which are not of functional consequence for the cells.
The second change is that we know more and more about the fact that cancer cells are undergoing such genome instability, meaning that they have adapted to cope with that. Cancer cells have often become dependent upon specific pathways that enable them to cope with genome instability that normal cells of the body don't require most of the time. This might give us a really good therapeutic window if we can target those pathways that cancer cells rely on, we might be able to kill those, whilst leaving normal cells untouched by those treatments.
The third aspect of cell biology that we know more about now is the 3D-structure of the nucleus. We now appreciate much more that although genes are arranged in linear fashion on DNA molecules, in the nucleus they are folded up in three dimensional organisation. That means that pieces of DNA which are far apart in linear space can be close together and regulate each other in three dimensional space, and this can influence cell behaviour in ways that we are only beginning to understand.

Q: Why does your line of research matter and why should we put money into it?

CG: Understanding the process of DNA replication is fundamentally important because of its contribution to genome instability. If we can understand how, when and why these mutagenic processes occur we might be able to devise, in the future, lifestyle interventions, treatments and alterations to reduce that mutational burden and reduce cancer formation. In the more immediate term many of the chemotherapeutics in use in the cancer clinics today target the process of DNA replication directly. They inhibit DNA replication, because cancer cells tend to be proliferating very rapidly and are doing a lot of DNA replication. If you can stop that then you can stop the cancer growing. But these drugs tend to have side-effects and if we understand more about the process of replication and how that process responds to these chemotherapeutic drugs we might be able to intervene in combination therapies, or in better drug design, to prevent some of these side-effects while maintaining cancer killing effects.

Q: How does your research fit into translational medicine within the Department?

CG: Most of the research that I and my group do would be classified as basic cellular research. We are trying to understand fundamental cell biology processes so that we can appreciate what has gone wrong when cancers develop, for example. Much of the understanding and development of cancer drugs in the last ten years have come from a basic improvement in our understanding of fundamental cell biology. The more we know about these pathways the more we can apply rational and targeted design of drugs and other interventions to stop cancers developing. As we identify new targets, new players, in these fundamental processes, it would be very easy to bring those in combination with these huge resources available in Oxford, to design and improve patient treatments in the future.

Catherine Green

Professor Catherine Green leads the Chromosome Dynamics group at the Wellcome Trust Centre for Human Genetics. She studies DNA replication forks, where genome instability is likely to arise and can lead to cancer or other disorders. She is particularly interested in processes that ensure genetic and epigenetic stability during DNA replication.

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