Crick group leader, Steve West, has been awarded the Royal Society’s prestigious Royal Medal for his research on DNA recombination and repair, as well as a new £734k grant from BBSRC to study key proteins involved in these processes. Here Steve tells us more about his research and recent awards.
What does your research focus on?
Our genomic material, DNA, is continually attacked by agents in the environment, such as radiation and pollution, and chemicals that we ingest in our diet. It also shows an inherent instability as it is replicated, transcribed or divided during cell division. It is estimated that, every day, a single human cell will suffer events leading to base damage, and single and double strand breaks in the chromosomal DNA.
If they are not repaired, these lesions accumulate and can lead to diseases such as cancer or progressive neurodegenerative disorders. To cope with such high levels of damage, our cells are equipped with a number of DNA repair mechanisms.
However, many individuals carry mutations that affect the efficiency of these DNA repair pathways. For example, individuals with mutations in the BRCA1, BRCA2, PALB2, or RAD51 genes are predisposed to breast and ovarian cancers. Mutations in the same genes can also cause Fanconi anaemia, a genetic disorder characterised by congenital abnormalities, progressive bone marrow failure and predisposition to head, neck and blood cancers. These genes encode proteins that promote the repair of DNA double-strand breaks, which represent possibly the most dangerous form of damage.
Our work aims to understand the process of DNA repair, in particular processes that promote the repair of DNA double strand breaks.
How do you feel about receiving this recognition from the Royal Society?
The award of a Royal Medal is something that I may have dreamed of but never thought would come true. A glance over the list of previous recipients leads to an escalation of my feelings of ‘imposter syndrome’ – my upbringing in a working-class family in a village in Yorkshire has always kept me well grounded, so I am deeply honoured by this award.
It is truly beyond anything that I could have imagined when I began my scientific career. Of course, my thanks go to my scientific father figures, Paul Howard-Flanders at Yale, and Tomas Lindahl at ICRF and CRUK, and of course to the many brilliant and energetic students and post-docs that have made my scientific journey such a pleasure. Without them I would not be here.
How will you be using the new grant?
With this new grant from BBSRC, we will aim to provide new insights into the mechanisms of DNA double-strand break repair. In particular, we’re looking at the structure and roles of key proteins in the repair process.
The structures of these proteins will be determined using a state-of-the-art technique called cryo-electron microscopy (cryo-EM). The proteins we are interested in will be purified away from all other cellular components, and then frozen well below -100 degrees so that they can be bombarded with electrons to produce microscopic images of individual molecules. These are used to reconstruct the 3D shape of the protein. Once we know their structure, we can start to understand why mutations compromise their activity and cause human disease.
These structural analyses will be supported by investigations into the protein’s mechanism of action. Together, our studies will provide detailed insights into why mutations in these important repair factors lead to human disease.
What else is the lab working on?
We are also identifying novel factors that act to promote DNA repair, and have recently discovered that inhibition of one such factor, called DNPH1, sensitises cancer cells to the drug Olaparib. This drug is currently used worldwide in the clinic for the treatment of breast and ovarian cancers, and we are trying to identify DNPH1 inhibitors that can be used to sensitise the cancer cells to the killing effect of Olaparib.