Epigenetics and Cancer: Determining how Mistakes in V(D)J Recombination Trigger Leukaemias and Lymphomas

Summary

V(D)J recombination is essential to produce an effective adaptive immune system but since the reaction involves breakage and rejoining of DNA, it is highly dangerous and errors have long been thought to lead to leukaemias and lymphomas. Recently, we uncovered a novel aberrant recombination reaction, named "cut-and-run" where the recombination by-product, in complex with the recombinase, triggers a series of double strand breaks throughout the genome. Crucially, these breaks correspond to some of those found in patients with Acute Lymphoblastic Leukaemia (ALL), suggesting that cut-and-run could play an important role in the development of ALL. This project aims to further investigate the cut-and-run reaction and whether it truly plays a role in the development of ALL with the longer term aim of developing novel cut-and-run inhibitors.

The four specific objectives are to:

1. Explore the extent to which cut-and-run breaks lead to cancer progression compared to other ways in which the by-product could cause cancer
2. Determine the level to which the recombination by-product is present in ALL patient samples and how it is distributed in the cancer
3. Further characterise the cut-and-run reaction to identify key differences from recombination and thus potential targets for inhibitors
4. Begin analysis of the recombination by-product/recombinase complex for longer term structural studies.

These studies will thus investigate a new mechanism by which a very frequent group of cancers is caused. In the longer term, it is hoped that these studies can help in the understanding of the risk factors, as well as the development of inhibitors, of these devastating diseases.

These studies will provide training in a broad range of modern techniques, including molecular biology, biochemistry, bioinformatics and preliminary structural biology analyses.

References

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• Burke, M.J., Scott, J.N., Minshull, T., Gao, Z., Manfield, I., Savic, S., Stockley, P.G., Calabrese, A. and Boyes J. (2022) A Bovine Antibody Possessing an Ultralong Complementarity-Determining Region, CDRH3, Targets a Highly Conserved Epitope on Sarbecovirus Spike Proteins. J. Biol. Chem. https://doi.org/10.1016/j.jbc.2022.102624
• Kirkham CM, Scott JNF, Wang X, Smith AL, Kupinski AP, Ford AM, Westhead DR, Stockley PG, Tuma R, Boyes JM (2019) Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability. Molecular Cell, Advanced online publication. https://doi.org/10.1016/j.molcel.2019.02.025
• Smith AL, Scott JNF and Boyes J (2019). The ESC: The Dangerous By-product of V(D)J Recombination. Front. Immunol. 10:1572. doi: 10.3389/fimmu.2019.01572
• Thwaites DT, Carter C, Lawless D, Savic S, Boyes JM. (2019) A novel RAG1 mutation reveals a critical in vivo role for HMGB1/2 during V(D)J recombination. Blood 133, 820-829. doi: 10.1182/blood-2018-07-866939

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