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


   Faculty of Biological Sciences

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

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.

Eligibility

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Biological Sciences minimum requirements in IELTS and TOEFL tests are:

  • British Council IELTS - score of 6.0 overall, with no element less than 5.5
  • TOEFL iBT - overall score of 87 with the listening and reading element no less than 20, writing element no less than 21 and the speaking element no less than 22. 

How to apply

To apply for this project applicants should complete an online application form and attach the following documentation to support their application. 

  • a full academic CV
  • degree certificate and transcripts of marks
  • Evidence that you meet the University's minimum English language requirements (if applicable)
  • Evidence of funding

To help us identify that you are applying for this project please ensure you provide the following information on your application form;

  • Select PhD in Biological Sciences as your programme of study
  • Give the full project title and name the supervisors listed in this advert

For information about the application process please contact the Faculty Admissions Team:

e:

For further details on the work in Dr. Boyes’ lab, please see:

https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/34/dr-joan-boyes

 For further information on the School of Molecular and Cellular Biology, please see: https://biologicalsciences.leeds.ac.uk/homepage/84/school-of-molecular-and-cellular-biology

Biological Sciences (4)

Funding Notes

This project is open to applicants who have the funding to support their own studies or who have a sponsor who will cover these costs.

References

Gao, Z., Wang, M, Smith, A.L. and Boyes J. (2023). YY1 binding to regulatory elements that lack enhancer activity promotes locus folding and gene activation. J. Mol. Biol. 435: 168315
Gao, Z., Smith, A.L., Scott, J.N.F., Bevington, S.L. and Boyes, J. (2023) Temporal analyses reveal a pivotal role for sense and anti-sense enhancer RNAs in coordinate immunoglobulin lambda locus activation. Nucleic Acids Research 51: 10344-10363.
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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