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Nucleases and helicases as potential cancer targets


   Department of Oncology

   Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

It is clear that the acquired genetic changes (vulnerabilities) in tumours can be exploited to treat cancer, increasingly in a manner tailored to individual patients. Defects and alterations in DNA repair pathways are often vital for tumour cell viability and are excellent potential therapeutic targets.

We are investigating a set of helicases and nucleases that directly execute pivotal steps in DNA repair reactions, incorporating basic science studies, extending across cell biology, biochemistry, chemical biology, and structural biology. The focus of this studentship will be the RECQL5 helicase, an enzyme that unwinds DNA structures to allow DNA repair to occur. RECQL5 performs its role in DNA repair in by cooperating with a nuclease complex, MUS81-EME1, capable of cutting DNA intermediates generated during repair reactions. Importantly, recent evidence from several laboratories, including our own, suggests that these factors might be particularly important for the survival of a subset of hard-to-treat breast tumours. Therefore, a detailed mechanistic understanding of the DNA repair pathways these factors control is urgently required in order to enable their therapeutic targeting.

We will explore the impact of RECQL5 loss in breast cancer cells, to characterise why the cells die using multiple cell biology approaches, including advanced imaging and genomic analysis. Using purified proteins, we will characterise the interactions between MUS81-EME1 and RECQL5, and define how the two factors cooperate during DNA repair reactions. We will attempt solve the structure of the RECQL5-MUS81 complex using cryo-electron microscopy. Working with collaborators in chemistry we will undertake screens for small molecule inhibitors of RECQL5 and using the identified hit compounds, evaluate the potential of RECQL5 inhibition as a therapeutic approach in breast cancer. The studentship will provide a broad training in cancer cell biology, biochemistry and early-phase therapeutic discovery.


References

Yosaatmadja, Y., Baddock, H.T., Newman, J.A., Bielinski, M., Gavard, A.E., Mukhopadhyay, S.M., Dannerfjord, A.A., Schofield, C.J., McHugh, P.J. and Gileadi, O., 2021. Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition. Nucleic acids research, 49(16), pp.9310-9326.
van Wietmarschen, N., Sridharan, S., Nathan, W.J., Tubbs, A., Chan, E.M., Callen, E., Wu, W., Belinky, F., Tripathi, V., Wong, N. and Foster, K., 2020. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature, 586(7828), pp.292-298.
Newman, J.A., Aitkenhead, H., Savitsky, P. and Gileadi, O., 2017. Insights into the RecQ helicase mechanism revealed by the structure of the helicase domain of human RECQL5. Nucleic acids research, 45(7), pp.4231-4243.

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