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

About the Project

V(D)J recombination is essential to produce antibody and T-cell receptor genes but since the reaction involves breaking and rejoining DNA, it is highly dangerous and errors have long been thought to lead to leukaemias and lymphomas. Recently, we discovered a novel way in which mistakes in V(D)J recombination lead to leukaemia. We named this reaction "cut-and-run" and found that the piece of DNA that is evicted from the genome during V(D)J recombination forms a complex with the RAG recombinase proteins. This complex then triggers double strand DNA breaks (DSBs) throughout the genome. Crucially, these DSBs correspond to some of the mutations found in patients with Acute Lymphoblastic Leukaemia (ALL), suggesting that cut-and-run plays an important role in the development of ALL. More recently, we discovered that cut-and-run also causes mutations in genes associated with relapse of ALL (Gao et al., Nature, 2025). This project aims to further investigate the cut-and-run reaction and why it shows increased targeting of relapse-associated genes in the patients who undergo relapse. This is important since relapse is the major cause of death of leukaemia patients. Our longer term aim is to develop ways to inhibit cut-and-run to prevent disease progression to relapse.

The specific objectives will build on our recent Nature paper to ask:

1. Why cut-and-run targets relapse-associated genes to a greater extent in some patients compared to others;
2. Determine how and why the recombination by-product persists in ALL patients. This is intriguing since the recombination by-product is a circular DNA that lacks a centromere but nonetheless appears to persist over many years;
3. Begin to analyse 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 international equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree.

If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements. The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid.

How to Apply

To apply for this project opportunity 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)

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 Biology as your programme of study
• Give the full project title and name the supervisors listed in this advert

Funding Notes

Due to funding limitations, only applicants with one of the following can be considered:

a) those with funding to support their own studies (stipend, university fees and bench fees)

b) those with a sponsor who will cover their stipend, university fees and bench fees

c) those who have identified fellowship/scholarship opportunities for which they can apply to support their studies and where the fellowship/scholarship will cover stipend, university fees and bench fees.