ZMBH Open PhD positions

Open PhD positions

Position no 1: Regulation of mRNA processing

In trypanosomes, RNA polymerase II transcription units are polycistronic. Individual mRNAs are excised by 5' trans splicing of a capped 39nt "spliced leader", and by polyadenylation. The polyadenylation of each mRNA is coupled to the splicing of the next mRNA downstream, and the splicing and polyadenylation complexes almost certainly physically interact. This project has two components:

  1. You will analyse the sequences that determine the efficiency of mRNA processing, using reporter constructs.
  2. You will investigate the interactions between the splicing and polyadenylation machineries
  3. You will screen for proteins that influence the trans splicing or polyadenylation efficiency/

This project is a collaboration with Shula Micahaeli, Bar Ilan University, Israel, and a collaborative visit to Israel is planned.

References:

  1. Clayton C (2016) Curr Opinion MIcrobiol 32: 46-51.
  2. Antwi E, et al. BMC Genomics 17: 306.
  3. Erben E, et al. (2014) PLoS Pathogens 10: e1004178.
  4. Gupta SK, et al. (2013) Nucleic Acids Res 41: 6577-6594.
  5. Michaeli S (2011) Future Microbiol 6: 459-474.
  6. Clayton C, Michaeli S (2011) Wiley Interdiscip Rev RNA 2: 247-255.

Position no 2: Roles of RNA-binding proteins in the control of trypanosome differentiation

Trypanosomes parasitise two organisms: mammals (where they are called "bloodstream forms") and tsetse flies (the form in the midgut is the procyclic form). We have found that the presence of an RNA-binding protein called RBP10 determines that the trypanosome is a bloodstream form. Repression of RBP10 expression in bloodstream forms initiates differentiation into procyclic forms, and expression of RBP10 in procyclic forms turns them into bloodstream forms. RBP10 acts by repressing other RNAs. It binds to the sequence UAUUUUUU in the 3'-untranslated regions of the target mRNAs, and both represses translation and stimulates mRNA degradation. Some of the target mRNAs also encode further RNA-binding proteins, so RBP10 changes initiate a regulatory cascade. This project has two elements:

  1. You will investigate how expression of RBP10 itself is regulated.
  2. You will investigate the functions of one of the RNA-binding proteins whose expression is controlled by RBP10.

A post-doc will also be working on other aspects of this project.

References:

  1. Clayton C (2016) Curr Opinion MIcrobiol 32: 46-51.
  2. Antwi E, et al. (2016) BMC Genomics 17: 306.
  3. Clayton CE (2014) Mol Biochem Parasitol 195: 96-106.
  4. Clayton C (2013) PLoS Pathog 9: e1003680.
  5. Wurst M, et al (2012) Mol Microbiol 83: 1048-1063.
  6. Mugo E & Clayton, C (2016) bioRxiv 076273; http://dx.doi.org/10.1101/076273

Position no 3: Identifying the targets of novel anti-trypanosomal compounds

Recently, over a million compounds have been screened to find out whether they kill trypanosomes or related parasites. 70 of these compounds are freely available for experimentation in the "Pathogen box". This project aims to define the mode of action of at least one of these compounds.

  1. You will screen the compounds to find out whether any of them affects gene expression. You will also design a microscopy-based screen that can be used for larger numbers of compounds. If results for any compounds are positive, you will investigate the mode of action in detail.
  2. You will use a new over-expression library to try to define the molecular target of at least one compound, either from (a), or by choosing one or two potent examples from the Pathogen box.

References:

  1. Begolo D et al (2014) Antimicrob Agents Chemother 58: 6260-6264.
  2. http://www.pathogenbox.org

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