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Molecular mechanisms of intron removal and spliceosome assembly

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  • Full or part time
    Dr Makarova
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

In eukaryotes, gene expression involves splicing, which is the removal of introns and joining together of exons in nascent pre-messenger RNA (pre-mRNA) to produce mature mRNA for protein production. The abundance of introns in mammalian cells, allows for a phenomenon called alternative splicing, which means that several different mature mRNAs can be produced from pre-mRNA transcripts originating from one gene. The spliceosome comprises of five small nuclear ribonucleic proteins (snRNP) and around two hundred other proteins. This complex of proteins is able to identify introns within pre-mRNA, catalyse the exclusion of the intron, and join flanking exons together through two trans-esterification reactions.
In my lab, we are interested in the initial steps of spliceosome assembly. We have previously isolated early (E) spliceosomal complexes and identified their protein composition. We now want to address the functional role of identified proteins in spliceosome formation and determine their mechanism of action at the molecular level. This is important because mutations in proteins of the E complex are linked to several cancers. We hope to use a multidisciplinary approach as part of this project that may include either of the following: structural studies (NMR and X-ray crystallography), fluorescent microscopy (FM), electron microscopy (EM), mass spectrometry (MS), and biochemical characterisation of protein-protein and RNA-protein interactions.
As part of the group, you will be trained in the expression and purification of proteins from bacterial and mammalian cultures; analysis of potential interacting partners using various methods including immunoprecipitation, mass spectrometry (MS) and western blotting; functional assays including depletion/reconstitution of splicing reactions, and RNA interference in cells; and novel methods such as CRISPR technology and live cell imaging could be employed to address the function in vivo.


We are an equal opportunities employer and particularly welcome applications for Ph.D. places from women, minority ethnic and other under-represented groups.

References

(1) Makarova, O. V. (2014) Spliceosome: the unravelling complexity. The Biochemist 36, 46-52.
(2) Makarov, E. M., Owen, N., Bottrill, A., and Makarova, O. V. (2012) Functional mammalian spliceosomal complex E contains SMN complex proteins in addition to U1 and U2 snRNPs. Nucleic Acids Res 40, 2639-52.
(3) Hernandez, H., Makarova, O. V., Makarov, E. M., Morgner, N., Muto, Y., Krummel, D. P., and Robinson, C. V. (2009) Isoforms of U1-70k control subunit dynamics in the human spliceosomal U1 snRNP. PLoS One 4, e7202.

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FTE Category A staff submitted: 37.40

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