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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
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Leukaemias and lymphomas are the fourth most common cancer with over 15,000 new cases per year in the UK alone. 35-40% of these cancers are thought to arise from mistakes in recombination reactions that produce antibody and T cell receptor genes. These recombination reactions mostly trigger cancer via chromosome translocations but recently, the DNA that is excised during V(D)J recombination also has been found to be a potent cause of cancer. Notably, the excised DNA can be re-integrated into the genome at recombination signal sequences (RSSs). This has the potential to cause cancer since the re-integrated DNA carries promoter elements and if re-integration occurs next to oncogenes, the oncogenes can become up-regulated, contributing to the development of lymphoid cancers. Importantly, the C-terminus of one of the recombinase enzymes carries a natural inhibitor of the re-integration reaction. This project will map the region within the recombinase that inhibits re-integration with the longer term goal of developing small molecule inhibitors of this highly dangerous reaction.

This project will:
1) Map the region of the recombinase C-terminus that inhibits re-integration
2) Perform detailed biochemical analyses of the reintegration reaction. The contacts between the recombinase and its substrates will be extensively probed to identify potential targets for inhibitors of re-integration.

Together, these studies will 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

References

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

Research output data provided by the Research Excellence Framework (REF)

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