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Building the chromosome segregation machinery from scratch


Laboratory of Molecular Biology

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Dr D Barford , Dr S Scheres No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Despite 130 years of research on mitosis, it is not clear how the mitotic spindle is assembled and how it obtains its characteristic bipolar shape that is critical for accurate chromosome segregation. It also remains unknown how a threshold force is reached and transmitted via kinetochore-fibers to split and segregate sister chromatids and how errors occur. Answers to these questions are needed to explain how cells divide and thus procreate life, and may provide new treatments for diseases that lie at the heart of cell proliferation, such as cancer and cell regeneration.

In order to address these questions, we study how the microtubule cytoskeleton builds the spindle, and pursue this subject by combining elements of cell biology, biochemistry, biophysics, structural biology and engineering. It has been established that multiple microtubule nucleation pathways independently generate the microtubules of the spindle. Yet, how these microtubule nucleation pathways are merged with one another to create a uniform spindle structure, remains a mystery. Interestingly, liquid-liquid phase transitions are critical as they modulate protein function during this process.

The PhD project builds upon our ability to reconstitute microtubule nucleation pathways in vitro. It involves using these pathways as pieces of a puzzle in order to pioneer building the chromosome segregation machinery from scratch and to further our understanding of how the spindle is made. This approach, in the absence of a cell membrane, enables the use of high-resolution light microscopy methods to capture the dynamics of individual microtubules, while applying cryo-electron tomography methods to resolve structural details. The project also relies on single particle cryo-electron microscopy, techniques at the interface of biochemistry and bioengineering, working with proteins undergoing condensation processes, and working in a vibrant team.

Funding Notes

https://www2.mrc-lmb.cam.ac.uk/students/international-phd-programme/funding/


References


Reviews

Prosser SL, Pelletier L. Mitotic spindle assembly in animal cells: a fine balancing act. Nat Rev Mol Cell Biol. 2017 Mar;18(3):187-201.

Petry S. Mechanisms of Mitotic Spindle Assembly. Annu Rev Biochem. 2016 Jun 2;85:659-83.

Kapoor TM. Metaphase Spindle Assembly. Biology (Basel). 2017 Feb 3;6(1):8.

Primary Literature

Alfaro-Aco R, Thawani A, Petry S. Biochemical reconstitution of branching microtubule nucleation. Elife. 2020 Jan 14;9:e49797.

King MR, Petry S. Phase separation of TPX2 enhances and spatially coordinates microtubule nucleation. Nat Commun. 2020 Jan 14;11(1):270.

Thawani A, Stone HA, Shaevitz JW, Petry S. Spatiotemporal organization of branched microtubule networks. Elife. 2019 May 8;8:e43890.

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