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


   Faculty of Biological Sciences

   Wednesday, June 01, 2022  Competition Funded PhD Project (UK Students Only)

About the Project

V(D)J recombination is essential to produce an effective adaptive immune system but since the reaction involves the 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) Determine if the genomic breakpoints identified in ALL cells are bona fide recombinase targets.

2) Determine if the recombination by-product is present in ALL patient samples and test how long the by-product persists in these cells.

3) Test if the recombination by-product can really lead to disease progression using a model system based on ALL-progenitor cells.

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.


Funding Notes

Funding for this project is via competition for an Endowed Scholarship. Information about the scholarships and how to apply is given via the links:
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Possible relevant scholarships.
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References

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.
Scott JN, Kupinski AP, Kirkham CM, Tuma R, Boyes J. (2014) TALE proteins bind to both active and inactive chromatin. Biochem J. 458:153-8. doi: 10.1042/BJ20131327.
Bevington, S., and Boyes, J., (2013) Transcription-coupled Eviction of histones H2A/H2B governs V(D)J recombination. EMBO J. 32:1381-92

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