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PhD Scholarships

4 Year CRUK PhD Studentship – September 2018 “Protein Phosphatase 2A in Cell Division and…

*4 Year CRUK PhD Studentship – September 2018*
_*“Protein Phosphatase 2A in Cell Division and Signalling”*_

*Cell Division Research Group – Professor Iain Hagan*

Protein phosphorylation is used widely to change the flux through the signalling pathways that determine cell fate. Consequently, the protein kinases that execute these phosphorylation events are frequently hyper-activated in cancer through mutation or overexpression and kinase inhibitors are widely deployed in cancer therapy. Although the phosphatases that remove the phosphate put on targets by kinases are mutated as frequently as kinases, far less is known about their biology. 95% of the serine/threonine phosphatase activity of a human cell is executed by protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). PP1, acts as a monomer that is recruited to defined docking motifs from where it dephosphorylates substrates. PP2A is a hetero-trimeric enzyme composed of single catalytic, structural and regulatory subunits. PP2A harbouring the B55 and B56 regulatory subunits execute many functions during cell division.

Commitment to mitosis is driven by Cdk1-Cyclin B kinase activation of a cohort of downstream kinases that drive chromosome condensation and formation of the mitotic spindle. Cyclin B is degraded once the chromosomes are correctly aligned in order to generate a state of low Cdk1-Cyclin B kinase activity that supports chromosome segregation into two daughter cells and exit from mitosis. These changes in protein kinase activity are coordinated with the equally important control of the counteracting protein phosphatase activities. Thus, while Cdk1-Cyclin B cannot drive cells into mitosis if the antagonistic PP2A-B55 phosphatase activity is not simultaneously repressed, PP2A-B55 activity is able to inappropriately drive cells out of division if Cdk1-Cyclin B activity declines below a critical threshold. Such inappropriate exit is known as mitotic slippage. The microtubule perturbing drug Taxol kills cells because it induces a sustained block to mitotic progression that triggers apoptosis to eliminate the cancerous cells. Some tumours resist killing by taxol because they slip out of mitosis before death can be triggered. Blocking PP2A-B55 activity in these cells would trap them in mitosis long enough to trigger death and so confer sensitivity to Taxol onto this cancer.

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We have used fission yeast as a model system in which to address the complex question of protein phosphatase function in cell division. We identified an unanticipated control of PP2A-B55 and PP2A-B56 by PP1 that appears to be conserved in humans (Grallert, Boke et al. 2015 Nature 517:94-98). The activity of all three phosphatases is repressed upon mitotic commitment. PP1 is inhibited through direct phosphorylation by Cdk1-CyclinB. Inhibition of PP2A-B55 and PP2A-B56 holo-enzymes is relieved by PP1 to promote exit from mitosis. PP1 recruitment to each PP2A complex is regulated. For PP2A-B56, PP1 recruitment is controlled via phosphorylation within the PP1 docking site, however it is unclear how PP1 recruitment to PP2A-B55 is modulated. PP1 only binds PP2A-B55 from mitotic commitment until the chromosomes are segregated in anaphase.
This studentship will address the hypothesis that phosphorylation of the B55 subunit modulates PP1 affinity. The native locus encoding fission yeast B55 will be mutated to change sites at which we have found phosphorylation to alanine/valine in order to block phosphorylation. The impact of each mutation on PP1 affinity and mitotic progression will be assessed. Sites that change affinity will be mutated to glutamic and aspartic acid, to mimic constitutive phosphorylation, and the functional analyses repeated. Antibodies that only recognise B55 when phosphorylated will monitor phosphorylation on key residues as cultures progress synchronously through division and determine the impact of mutating the 106 kinases of fission yeast upon phosphorylation at this site. The impact of phosphorylation upon phosphatase activity will be assessed with established assays, while a combination of in vitro biochemistry and in vivo cell biology will determine how the identified kinase controls phosphorylation at this site in different signalling contexts.
Of the 8 sites of phosphorylation that we have identified on fission yeast B55, 7 are conserved in humans. Once the work in fission yeast has identified which sites play defining roles in controlling PP2A-B55 function, genome editing with CRISPR-cas9 technology will mutate the loci encoding B55 in h-TERT immortalised human RPE-1 diploid cells. The impact of phospho-mimetic and phospho-blocking mutations upon PP2A-B55 function will be monitored with a range of biochemical and cell biological assays. Antibodies that recognise the target site when phosphorylated will be generated to chart the timing of modification and identify the kinase responsible for phosphorylating the residue and interrogate the relevant signalling network in normal and transformed cells.

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Informal enquiries should be addressed to Professor Iain Hagan; [email protected]

Interested students can find full group project details, entry criteria and details on how to apply on the CRUK Manchester Institute website;

*Closing date: Friday 19 January 2018, 2400 hrs (GMT)*
*Interview date: Wednesday 14 February 2018, Alderley Park, Cheshire*

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PhD Scholarships

PhD positions at The University of Warwick : Biological Sciences/Synthetic biology (# of pos: 4)

Our group is offering PhD positions for 2018-2019 academic year.  These studentships are hosted by The University of Warwick Doctoral Training Centres 

 Details below

1) PhD project title: Engineering microbial chemical factories to produce renewable and modified biomaterials. 

PhD is hosted via MIBT Partnership

Research Area  : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :-

2) PhD project title: Development of novel halogenase enzymes for biopharmaceutical applications.

PhD is hosted via MIBT Partnership

Research Area : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :-

3) PhD project title: Expanding the genetic lexicon: Developing novel tools for non-natural amino acid incorporation in to therapeutic peptides and proteins.

PhD is hosted via SynBIO DTC 

Research Area : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :-

4) PhD project title:  Bioplastics from E. coli

PhD is hosted via SynBIO DTC

Research Area : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :-

Applications are encouraged from UK, EU and International students.

Please be aware that International (non EU) applicants are not eligible for EPSRC/BBSRC funded studentships.

To be eligible for a full EPSRC/BBSRC award (Tuition fees and Stipend) a student must have:

  • Settled status in the UK, meaning they have no restrictions on how long then can stay and
  • Been ‘ordinarily resident’ in the UK for 3 years prior to the start of the studentship. This means they must have been normally residing in the UK (apart from temporary or occasional absences) and
  • Not been residing in the UK wholly or mainly for the purpose of full-time education. (This does not apply to UK or EU nationals).
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To be eligible for an EPSRC/BBSRC tuition fees only award:

  • Students from EU countries other than the UK are generally eligible for a fees-only award. To be eligible for a fees-only award, a student must be ordinarily resident in a member state of the EU, in the same way as UK students must be ordinarily resident in the UK.

Interested students with research experience and qualification please contact us directly.

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France Scholarships

PhD position in quantum optimal control theory at the University of Bourgogne

This PhD project aims at applying innovative mathematical tools coming

from optimal control theory to improve theoretical and experimental techniques

in Nuclear Magnetic Resonance (NMR), in Electron Spin Resonance (ESR) and in NV

centers. This approach will allow us to explore and to experimentally reach the

physical limits of the corresponding spin dynamics in presence of typical

experimental imperfections and limitations. A first objective will be to

develop new optimal control algorithms able for an inhomogeneous ensemble of

spins to maximize the signal to noise ratio per unit time of the system. A

general problem is to generalize the Ernst angle solution used in NMR, which is

only valid for a homogeneous spin ensemble. This work will be done in

collaboration with the group of S. Glaser (TUM, Munich, Germany). This approach

will find different applications in NMR and ESR where the sensitivity of the

experiment is a crucial parameter. The student will focus on a specific

experimental setup in ESR used by the group of P. Bertet (CEA, Paris Saclay),

where an important goal is the maximization of the emitted signal of spins

coupled to a microwave resonator. The student will take into account in the

numerical computation specific constraints of this experimental setup. In the

same direction, the student will also use optimal control techniques to design

new CMPG sequences accounting for the coupling between the spins and the

cavity. The same types of control techniques will also be used for manipulating

NV ensembles in collaboration with the group of T. Debuisschert (Thalès,

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Paris). This will allow the improvement of the sensitivity of the corresponding

experiments. For a more fundamental point of view, the ESR will investigate the

numerical techniques used to design robust control fields with respect to

experimental imperfections. A first objective will be to understand the

efficiency of these methods and to prove the optimality (this concept will be

to define rigorously) of the control fields. The ESR will mainly study spin

systems but it is clear that the results of this project will not be restricted

to the physical systems investigated and the techniques developed during the

PhD could be applied to other physical systems with similar properties.

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Israel Scholarships

Marie Curie Innovative Training Network (ITN) META-CAN – PhD position in Computational biology to…

The Machine Learning for Healthcare and Life Sciences group at IBM Research – Haifa is a partner in the funded Marie Curie Innovative Training Network (ITN) META-CAN. The network is a pan-European interdisciplinary and intersectoral training programme for excellence.  It brings young researchers together with world-leading academics, clinicians, and industry personnel to focus on the connections of metabolism, immune response, and cancer.

We are looking for an enthusiastic and highly-motivated early stage researcher (ESR), with a background and experience in computational biology, machine learning and/or statistics and good programming skills (preferably in Python or R). This ESR will study towards a PhD degree and, under our guidance (and in collaboration with the Technion Integrated Cancer Center), will analyze comprehensive omics data to better understand the metabolic adaptations of cancer cells to the central nervous system niche.

The right candidate will enjoy a competitive salary and outstanding work environment.

For more details see  or contact [email protected]

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