PhD position to study the mechanisms of chromosome segregation (f/m/x)

The JP lab (Twitter @JPLab_) which will start in March 2023 his ERC funded group at the Gene Center of the Ludwig-Maximilians University Munich (LMU) has an opening for a highly motivated PhD candidate with the necessary training to work on mechanisms of chromosome segregation using structural and cell biological methods.

PhD position to study the mechanisms of chromosome segregation (f/m/x)

Cell division is a fundamental biological process essential for organismal growth and repair. Understanding the molecular mechanisms of accurate chromosome segregation is crucial as defects in this process often result in daughter cells with inappropriate chromosome numbers, a state called aneuploidy which is a hallmark of cancer. To ensure accurate cell division, the genetic information, which is in the form of chromosomes, needs to be distributed equally to the newly formed daughter cells.

Some of the key molecular processes essential for error-free chromosome segregation are:

• physical attachment of chromosomes to the microtubule-based segregation machinery called the mitotic spindle and
• holding the sister chromatids together until all chromosomes (sister chromatid pairs) establish biorientation, where sister chromatids attach to microtubules emanating from opposite spindle poles.

These processes are tightly regulated, both in space and time, by intricate protein interaction networks involving several multi-subunit protein assemblies such as the Chromosomal Passenger Complex, Cohesin, protein phosphatases, PP2A/B56. However, a precise structural understanding of how these key players interact with and regulate each other remains unclear.

One of the major challenges limiting the structural characterisation of these protein complexes is that the protein subunits constituting them are generally modular in nature with more than one globular domain connected by intrinsically unstructured linker regions, thus conferring flexibility and conformational heterogeneity. To overcome this, this project will employ an integrative structural approach by combining experimental structural biology methods, such as X-ray crystallography, cryogenic electron microscopy (cryoEM), small angle X-ray scattering (SAXS), and cross-linking mass spectrometry (CLMS), with computational techniques including ab-initio structure prediction, molecular docking, multiscale modelling and molecular dynamics simulations. These structural analyses will allow us to perturb specific intermolecular interactions in vitro and in human cell lines (functional rescue assays) to evaluate the roles of specific intermolecular interactions in achieving accurate chromosome segregation. Overall, this integrative structure-function approach will provide novel mechanistic insights into the regulation of chromosome segregation.

References

1. Abad, M. A*., Gupta, T*., Hadders, M, A., Meppelink, A., Wopken, J. P., Blackburn, E., Zou, J., Gireesh, A., Buzuk, L., Kelly, D, A., McHugh, T., Rappsilber, J., Lens, S. M. A and Jeyaprakash, A. A. Mechanistic Basis for Sgo1-Mediated Centromere Localisation and Function of the CPC. J. Cell Biol (2022) 221(8):e202108156  (*equal contibution)

2. Thamkachy R*, Medina-Pritchard B*, Park SO*, Chiodi CG, Zou J, de la Torre-Barranco M, Shimanaka K, Abad MA, Páramo G, Feederle R, Ruksenaite E, Heun P, Davies OR, Rappsilber J, Schneidman-Duhovny D, Cho U-S and Jeyaprakash AA. Structural Basis for Mis18 Complex Assembly: Implications for Centromere Maintenance. bioRxiv (2021)  (*equal contribution)

3. Medina-Pritchard B, Lazou V, Zou J, Byron O, Maria A Abad, Rappsilber J, Heun P and Jeyaprakash AA (2020). Structural Basis for Centromere Maintenance by Drosophila CENP-A chaperone Cal1. EMBO J. 39:e103234

4. Abad MA, Ruppert JG*, Buzuk L*, Wear M, Zou J, Webb KM, Kelly DA, Voigt P, Rappsilber J, Earnshaw WC and Jeyaprakash AA (2019) Borealin-Nucleosome Interaction Secures Chromosome Association of the Chromosomal Passenger Complex. J Cell Biol.  (*equal contribution)

5. Abad, M. A., Medina, B., Santamaria, A., Zou, J., Plasberg-Hill, C., Madhumalar, A., Jayachandran, U., Redli, P. M., Rappsilber, J., Nigg, E. A. and Jeyaprakash. A. A. Structural Basis for Microtubule Recognition by the Human Kinetochore Ska Complex. Nat Commun (2014) Jan13; 5:2964.

Your profile

• Outstanding degree (MSc) in the area of biochemistry, molecular biology, structural biology, biology, or similar
• Excellent communication skills, fluency in English (written and oral)
• Solid experience in biochemical and cell biology techniques (recombinant protein purification, mammalian cell culture, immunofluorescence, molecular cloning, PCR, immunoblotting)
• Prior experience in strucutral characterisation of protein assemblies using cryoEM or/and crystallography preferred

Our offer

We are based at the Gene Center Munich. Our group is embedded in the stimulating, interdisciplinary environment of the life sciences campus Großhadern of the Ludwig-Maximilians University Munich (LMU). Downtown Munich can be reached by public transport within 20 minutes, the German Alps in just over 1 hour. The position is initially limited to three years, with a possibility of extension. Salary is determined by prior experience according to the German public sector pay scale TV-L.

Application

The application should be submitted as a single PDF including a CV, a letter of motivation and contact information for 2 references. Please send your application to jeyapra@ed.ac.uk. The University of Munich is an equal opportunity employer. Handicapped candidates with equal qualifications will be given preference.

For more information about our lab and our research please visit our Gene Center website  as well as our University of Edinburgh website. The Gene Center hosts the ERC-funded research of the JP lab. Hence, the JP will run two labs (Edinburgh and Munich) during the course of the ERC grant. This offers great opportunities for the successful PhD student to visit the Edinburgh lab and carry out specialised cell biology aspects of the research as and when required.

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