About the Project
Interested individuals must follow Steps 1, 2 and 3 at this link on how to apply
http://www.ed.ac.uk/biology/prospective-students/postgraduate/pgr/how-to-apply
Transposons make up a large proportion of most genomes and can move from one place to another, driving evolution and creating genome instability. Jumping genes have also given rise to new, useful cell functions e.g. V(D)J recombination and the adaptation process of CRISPR-Cas adaptive immunity. Eukaryotic DNA transposons (including Sleeping Beauty) are also useful tools for genomic manipulations. At the mechanistic level, DNA transposition is related to HIV-1 integration and V(D)J recombination.
To establish in molecular detail how DNA transposons move, we are characterising the structures of nucleoprotein complexes that form along the transposition pathway of the mariner/Tc1 transposon Mos1. In this way we have shown how the transposon is cut from host DNA1, and how the ends are held together2 and then inserted at a new genomic location. Most recently we have discovered a bend, flip and trap mechanism for transposon integration at TA sites3.
Our aim now is manipulate the transposase enzymes so that transposon integration can be (a) targeted to specific DNA sequences or (b) randomised. Our findings should be directly applicable to other mariner/Tc1 transposases, e.g. Sleeping Beauty, which is being used in human clinical trials to treat B-cell lymphoma by genetic engineering of T cells and in pre-clinical studies to reduce age-related macular degeneration. These findings have implications for our understanding of DNA rearrangements more broadly and will advance biotechnology applications of transposons.
The student will develop a broad range of skills in structural biology, biochemistry and molecular biology. Laboratory skills developed will include protein expression and purification; transposase-DNA cleavage, binding and integration assays; structure determination of transposase DNA complexes by X-ray crystallography; fluorescence spectroscopy.
More information about the lab, our interests and publications can be found here: http://richardson.bio.ed.ac.uk/
References
1.Structural role of the flanking DNA in mariner transposon excision
Dornan,">http://www.research.ed.ac.uk/portal/en/persons/jacqueline-dornan(1afcca25-ecbe-41fc-a574-e78824483e53).html">Dornan, J., Grey,">http://www.research.ed.ac.uk/portal/en/persons/heather-grey(1a492055-1d80-48d1-a649-d6a55d580e17).html">Grey, H. & Richardson,">http://www.research.ed.ac.uk/portal/en/persons/julia-richardson(f907716c-7188-4ac9-8b67-a942b3433950).html">Richardson, J. M. (2015) Nucleic Acids Research. 43(4) 2424-2432
2.Molecular Architecture of the Mos1 Paired-End Complex: The Structural Basis of DNA Transposition in a Eukaryote
Richardson,">http://www.research.ed.ac.uk/portal/en/persons/julia-richardson(f907716c-7188-4ac9-8b67-a942b3433950).html">Richardson, J. M., Colloms, S. D., Finnegan, D. J. & Walkinshaw,">http://www.research.ed.ac.uk/portal/en/persons/malcolm-walkinshaw(56f81307-b59d-4f67-a443-cd3bb78cde83).html">Walkinshaw, M. D. (2009) Cell. 138, (6), 1096-1108
3.A bend, flip and trap mechanism for transposon integration
Morris,">http://www.research.ed.ac.uk/portal/en/persons/elizabeth-morris(dc13b2b4-5b17-4b9a-a640-44a38fb5bc89).html">Morris, E., Grey,">http://www.research.ed.ac.uk/portal/en/persons/heather-grey(1a492055-1d80-48d1-a649-d6a55d580e17).html">Grey, H., McKenzie, G., Jones,">http://www.research.ed.ac.uk/portal/en/persons/anita-jones(ab42ddb3-a4a2-404a-a271-76acae3639bd).html">Jones, A. & Richardson,">http://www.research.ed.ac.uk/portal/en/persons/julia-richardson(f907716c-7188-4ac9-8b67-a942b3433950).html">Richardson, J. (2
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