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

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

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

Please contact Dr. Boyes directly for an explanation of funding schemes and deadlines

References

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 in press 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

de Thonel, A., Vandekerckhove, J., Lanneau, D., Selvakumar, S., Courtois, G., Hazoume, A., Brunet, M., Maurel, S., Hammann, A., Ribeil, J.A., Zermati, Y., Gabet, A.S., Boyes, J., Solary, E., Hermine, O., Garrido, C. (2010) HSP27 controls GATA-1 protein level during erythroid cell differentiation. Blood. 116, 85-96.

Palacios, D., Summerbell, D., Rigby, P.W.J. and Boyes, J. (2010) Interplay between DNA Methylation and Transcription Factor Availability: Implications for Developmental Activation of the Mouse Myogenin Gene. Molecular and Cellular Biology. 30, 3805-3815.

*Baumann, M., *Nightingale, K., Eberharter, A., Mamais, A., Becker, P., and Boyes, J. (2007) Acetylation Stimulates V(D)J Recombination by Regulating Accessibility to Nucleosome Remodelling Complexes. Nucleic Acids Research. 35, 6311-21.

Hernandez-Hernandez, A., Ray, P., Litos, G., Ciro, M., Ottolenghi, S., Beug, H., and Boyes J. (2006) Acetylation and MAPK Phosphorylation Co-operate to Regulate the Degradation of Active GATA-1 EMBO J. 25, 3264-74.

Baumann M, Mamais A, McBlane F, Xiao H, Boyes J. (2003) Regulation of V(D)J recombination by nucleosome positioning at recombination signal sequences. EMBO J. 22:5197-207.

McBlane F, Boyes J. (2000) Stimulation of V(D)J recombination by histone acetylation. Curr Biol. 10:483-6.

Boyes, J., Byfield, P., Nakatani, Y. and Ogryzko, V. (1998) Regulation of GATA-1 Activity by Acetylation. Nature, 396: 594-598.

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

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