AVÊÓƵ

DNA replication and genetic stability

Understanding the mechanisms that underlie the accuracy of DNA replication and repair, the consequences for genetic integrity when these mechanisms fail and how this can cause human disease is the rationale for the work of the Medical Research Council's Genome Damage and Stability Centre (GDSC) at the AVÊÓƵ.

Genome Damage and Stability Centre

The research of the GDSC presents important opportunities in translational drug discovery and the application of basic and clinical research, particularly in the treatment of cancer.

DNA is fundamental to all living organisms and is often damaged and changed by agents in the environment. When DNA is damaged it is also hard to replicate (duplicate).

DNA replication involves the complete and accurate copying of the entire genome in one cell, which is followed by the process of mitosis (cell division) and the generation of two cells.

This process is essential for tissue repair, organogenesis, and embryonic development – that is, it is fundamental to the continuation of life.

Failure or dysfunction in DNA repair mechanisms or replication itself results in genetic mutations or gross chromosomal rearrangements (including duplications, deletions and amplifications) that are the basis of many disease states including cancer, developmental disorders and, potentially, neurodegenerative disorders associated with old age.

Understanding the fundamental mechanisms of action of DNA repair and replication and how they interact, as well as the consequences of defects in these systems for genetic integrity, provides insight into how associated human diseases might arise and, ultimately, be treated.

Investigating how cells maintain their genetic integrity

The GDSC, directed by Professor Anthony Carr, comprises 18 different research groups investigating many different aspects of how cells maintain their genetic integrity and the potential impact on human disease.

The work of Professor Carr's laboratory focuses on the relationship between DNA replication and the accumulation of genetic mutations. Errors in replication lead to a high proportion of the mutations in our cells, including gross chromosomal rearrangements.

How the cell responds to damage during replication is important in understanding how disease develops.

DNA replication is initiated at specific locations, the origin of replication, in the genome and begins by the unwinding of the two strands of the double helix followed by the template synthesis of two new strands of DNA, resulting in two identical double helices.

The point of strand separation and synthesis forms a replication 'fork', which is associated with the many proteins of the replication 'machine'.

When the replication fork meets DNA damage, or spontaneously stops working, the cell tries to overcome this by restarting replication to copy that piece of DNA by reassembling a replication machine at the replication fork.

To study this mechanism, Professor Carr's laboratory have developed a replication fork arrest system in the fission yeast model Schizosaccharomyces pombe that allows them to control replication arrest and study how cells respond to correct the problem.

Using this system, they have demonstrated several important findings relating to this process. This includes recent work, published in Nature (January 2013), showing that even when replication restarts at the correct point, errors (mutations) arise in the DNA synthesised by the newly started replication machine.

Through their work they have seen many of the mutations types commonly observed in cancer, and, interestingly, they are also beginning to see changes in the proteins that make up the replication machine at the restarted replication fork.

This project is typical of the collaborative nature of work in the GDSC; carried out in partnership with another group in the GDSC, led by Dr Johanne Murray, and Dr Sarah Lambert at the Institut Curie in Paris, and using technology implemented in collaboration with Dr Mark Osborne in the Department of Chemistry.

Studying genetic diseases

Part of the GDSC's research involves studying genetic diseases, including cancers, where DNA repair/replication systems and cell division and proliferation are faulty.

Such work directly impacts how we treat disease, as illustrated by a new discovery recently published in the prestigious Nature Chemical Biology (March 2013) and co-authored by Laurence Pearl FRS, Professor of Structural Biology in the GDSC and Head of the School of Life Sciences.

The anti-cancer drug class of kinase inhibitors are among the many novel clinical agents, licensed and under development, which take a new targeted approach to drug design.

However, while there are many cancer patients who might benefit from treatment with kinase inhibitors – these drugs work across many cancer types, including breast, skin, lung and kidney – they often only extend life by around three to six months.

This newly published research, funded by Cancer Research UK and the Wellcome Trust, has uncovered a novel mechanism of action that may unlock the true potential of these drugs by changing the way they are used.

In addition to their known mechanism of action, at high doses they also prevent kinases from linking up with a complex of molecules in cells called the Hsp90-Cdc37 chaperone system, which is essential for maintaining the stability of proteins.

This 'chaperone deprivation' destroys cancercausing kinases and halts the growth and division of cancer cells. Clinical studies that take advantage of this new mechanism are now underway to determine whether they can keep cancers at bay for longer.

The AVÊÓƵ has made a considerable commitment to a wider translational science agenda in recent years, as illustrated by the investment in a new Translational Drug Discovery Group, established at the end of 2010 and directed by Professors Simon Ward and John Atack, both of whom have an extensive track record of leading industry drug discovery teams from initial ideas through to clinical trials.

The work of the GDSC presents excellent opportunities to fulfil this agenda and forge collaborations within the University that cross over from basic and clinical research into translational drug discovery.