Chromosome Segregation Laboratory   

Andrew McAinsh - Group Leader Ainslie Garrod, BSc Catarina Samora, BSc                                           For more information please visit our Laboratory website With immediate effect we have moved! Our new contact details are as follows: Clinical Sciences Research Institute Room B0-38 Clinical Sciences Research Institute Warwick Medical School University of Warwick Coventry CV4 7AL Tel: 024 7515 1168 Fax: 024 7652 8375 Email: A.D.McAinsh@warwick.ac.uk http://www.mechanochemistry.org Accurate chromosome segregation is crucial for producing the correct number of chromosomes in each daughter cell following mitosis. It has been known for over 100 years that an abnormal number of chromosomes (known as aneuploidy) is a common characteristic of cancer cells. We now know that >80% of solid tumours in humans are aneuploid suggesting a fundamental link between errors in chromosome segregation and tumour development. Chromosome segregation requires attachment of chromosomes to the microtubules of the mitotic spindle, their alignment on the metaphase plate, and their subsequent segregation between the two daughter cells during anaphase. Attachment of chromosomes to microtubules requires amazing machines known as kinetochores, which are built from at least 100 different protein components. As well as binding to microtubules, kinetochores are responsible for generating the forces required to power chromosome movements during mitosis. Kinetochores can also "sense" if they are improperly attached to microtubules and produce a "wait!" signal that prevents anaphase onset until all kinetochores, and thus chromosomes, have become correctly attached. We are using a combination of biochemistry, genetics and microscope-based assays to investigate the protein composition and architecture of human kinetochores and determine how they work at the molecular level. We hope to use this knowledge to identify novel therapeutic routes that would allow the inhibition of mitosis in aneuploid cells.

 

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Selected references:

†corresponding author;  *These authors contributed equally to this work

McClelland, S.E. and McAinsh, A.D.  (2009)  Hydrodynamic analysis of human kinetochore complexes during mitosis.  Methods Mol. Biol., 545: 81-98.

Braun, M., Drummond, D.R., Cross, R.A. and McAinsh, A.D.  (2009) The kinesin-14 Klp2 organizes microtubules into parallel bundles by an ATP-dependent sorting mechanism. Nature Cell Biol. 11: 724-730.

*Toso, A., Winter, J., Garrod, A.J., Amaro, A.C., †Meraldi, P. and †McAinsh, A.D. (2009) Kinetchore-generated pushing forces separate centrosomes during bipolar spindle assembly. J. Cell Biol., 184: 365-372.

*McClelland, S.E., *Borusu, S., Amaro, A.C., Winter, J.R., Belwal, M., †McAinsh, A.D. and †Meraldi, P. (2007) The CENP-A NAC/CAD kinetochore complex controls chromosome congression and spindle bipolarity. EMBO J., 26: 5033-5047.

Porter, I.M., McCelland, S.E., Khoudoli, G.A., Hunter, C.J., Andersen, J.S., McAinsh, A.D., Blow, J. and Swedlow, J.R. (2007) Bod1, a novel kinetochore protein required for chromosome biorientation. J. Cell Biol., 179: 187-197.

Przewloka, M.R., Zhang, W., Costal, P. Archambault, V., D'Avino, P.P., Lilley, K.S., Laue, E.D., McAinsh, A.D. and Glover, D.M.  (2007) Molecular analysis of core kinetochore composition and assembly in Drosophila melanogaster. PLoS ONE, 5:e478.

*†McAinsh, A.D., *†Meraldi, P., *Draviam, V.M., Tosa. A. & Sorger, P.K. (2006)
The human kinetochore proteins Nnf1R and Mcm21R are required for accurate chromosome segregation. EMBO J., 25: 4033-4049.