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Epigenetics and Cancer: Development of Novel Tools to Determine how Aberrant V(D)J Recombination Reactions Cause Leukaemia


Faculty of Biological Sciences

About the Project

V(D)J recombination generates a highly diverse set of immunoglobulin and T cell receptor genes to enable vertebrates to fight a vast range of infections. However, since the reaction involves the breakage and rejoining of DNA, it is inherently risky and between 35-40% of lymphoid cancers are thought to have arisen from mistakes in V(D)J and related recombination reactions. Since there are over 15,000 new cases of lymphoid cancer per year in the UK alone, there is a strong need to better understand what causes these aberrant recombination reactions

We have now developed a novel inducible V(D)J recombination system in which recombination can be activated at will. This project will use the inducible recombination system to examine the safeguards that prevent chromosome translocations during V(D)J recombination. The project will utilize state-of-the-art technologies to give the student first class training in modern molecular, cellular and cancer biology. It will focus on the epigenetic and transcriptional regulation of V(D)J recombination and how errors in this process lead to leukaemia.

References

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

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.

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


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.


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