Key facts
- Type of research degree
- PhD
- Application deadline
- Ongoing deadline
- Country eligibility
- International (open to all nationalities, including the UK)
- Funding
- Non-funded
- Supervisors
- Dr Joan Boyes
- Schools
- School of Molecular and Cellular Biology
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.
<p>The four specific objectives are to:</p> <ol> <li>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</li> <li>Determine the level to which the recombination by-product is present in ALL patient samples and how it is distributed in the cancer</li> <li>Further characterise the cut-and-run reaction to identify key differences from recombination and thus potential targets for inhibitors</li> <li>Begin analysis of the recombination by-product/recombinase complex for longer term structural studies.</li> </ol> <p>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.</p> <p>These studies will provide training in a broad range of modern techniques, including molecular biology, biochemistry, bioinformatics and preliminary structural biology analyses.</p> <p>References</p> <ul> <li>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.</li> <li>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.</li> <li>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</li> <li>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</li> <li>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</li> <li>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</li> </ul>
<p>To apply for this project opportunity applicants should complete an <a href="https://biologicalsciences.leeds.ac.uk/research-degrees/doc/how-to-apply">online application form</a> and attach the following documentation to support their application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks</li> <li>Evidence that you meet the University's minimum English language requirements (if applicable)</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Biology as your programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>
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. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.
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. Some schools and faculties have a higher requirement.
<p>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.</p> <p> </p>
<p>For information about the application process please contact the Faculty Admissions Team:</p> <p>e: <a href="mailto:fbsgrad@leeds.ac.uk">fbsgrad@leeds.ac.uk</a></p>