RESEARCH PROFILE

Cell division is fundamental to the existence of life. A key part of this process involves the accurate separation of the chromosomes into the two daughter cells - a process called mitosis. Errors in chromosome segregation drive chromosomal instability, aneuploidy and cancer development. Dr. McAinsh's lab of graduate students, postdoctoral fellows and technicians are focused on understanding the mechanisms by which kinetochores power chromosome segregation and how the mitotic spindle is self-assembled and positioned during mitosis in human cells. Approaches in the McAinsh lab include live-cell microscope-based assays, computational image analysis and in vitro reconstitution.

BACKGROUND

CURRENT RESEARCH PROJECTS

• Mechanisms of spindle checkpoint silencing, with Professor Jonathan B Millar, Biomedical Cell Biology, Funded by: MRC, Project Start Date: 01/10/2012 Project End Date: 30/09/2017
• System-mechanics of the kinetochores: operating principles of a complex mechanochemical engine., with Prof. Nigel Burroughs (Warwick Systems Biology Centre), Funded by: BBSRC, Kinetochores are adaptive, multi-layered mechanochemical machines that assemble at the centromere of each sister chromatid and engage on their outer face with the plus ends of k-fibres, microtubule bundles that emanate from the spindle poles. We envision the kinetochore as a set of interacting springs, clutches and motors and the problem of kinetochore mechanism as one of understanding how these functional modules assemble, disassemble and interact with one another to give rise the emergent properties of the kinetochore. Incisive experiments made over 17 years ago revealed that once sister kinetochores become attached to microtubules emanating from opposite poles (biorientation), they undergo a series of oscillations - termed chromosome directional instability - prior to anaphase onset. However, neither the mechanisms nor purpose of kinetochore directional switching in human cells is well understood. We propose a parallel approach employing mathematical modeling in tandem with higher-resolution tracking experiments of both native kinetochores and kinetochores specifically depleted of specific protein components. Oscillation is a high-level emergent property, providing a read-out of functional competence and a stringent quantitative test for the accuracy of our model. Iteratively refining the model in the light of our real-world data on oscillations will enumerate and deconvolve the contributions of mechanical components of the kinetochore to its emergent behaviour. We also expect to provide the first insight into the function of chromosome oscillations in animal cells., Project Start Date: 01/07/2011 Project End Date: 30/06/2015
  
  

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SELECTED PUBLICATIONS

• Earnshaw WC, Allshire RC, Black BE, Bloom K, Brinkley BR, Brown W, Cheeseman IM, Choo KH, Copenhaver GP, Deluca JG, Desai A, Diekmann S, Erhardt S, Fitzgerald-Hayes M, Foltz D, Fukagawa T, Gassmann R, Gerlich DW, Glover DM, Gorbsky GJ, Harrison SC, Heun P, Hirota T, Jansen LE, Karpen G, Kops GJ, Lampson MA, Lens SM, Losada A, Luger K, Maiato H, Maddox PS, Margolis RL, Masumoto H, McAinsh AD, Mellone BG, Meraldi P, Musacchio A, Oegema K, O'Neill RJ, Salmon ED, Scott KC, Straight AF, Stukenberg PT, Sullivan BA, Sullivan KF, Sunkel CE, Swedlow JR, Walczak CE, Warburton PE, Westermann S, Willard HF, Wordeman L, Yanagida M, Yen TJ, Yoda K, Cleveland DW. (2013) 'Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant.' Chromosome Research
• Cheeseman LP, Harry EF, McAinsh AD, Prior IA, Royle SJ. (2013) 'Specific removal of TACC3/ch-TOG/clathrin at metaphase deregulates kinetochore fiber tension.' Journal Of Cell Science
• Drechsler, H. and McAinsh, A.D. (2012) 'Exotic Mitotic Mechanisms' Open Biology 2 120140 [article]
• Eskat A, Deng W, Hofmeister A, Rudolphi S, Emmerth S, Hellwig D, Ulbricht T, Doring V, Bancroft JM, McAinsh AD, Cardoso MC, Meraldi P, Hoischen C, Leonhardt H, Diekmann S. (2012) 'Step-Wise Assembly, Maturation and Dynamic Behavior of the Human CENP-P/O/R/Q/U Kinetochore Sub-Complex.' PLoS One 7 (9), e44717 [article]
• Cross, R.A., McAinsh, A.D., Straube, A. (2011) 'Mechanochemical cell biology.' Seminars In Cell And Developmental Biology 913 - 915

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Conferences

RESEARCH DEGREES SUPERVISED

• Mechanical deformations in kinetochores during directed chromosome motion, Date of Completion: 2015
• Molecular analysis of the human kinetochore proteins CENP-P and CENP-Q, Date of Completion: 2013
• Chromosome Navigation: finding the way to the spindle equator, Date of Completion: 2013
• Molecular analysis of kinetochore-microtubule dynamics and mitotic spindle positioning, Date of Completion: 2012
• Biochemical Characterisation of the S. pombe Kinesin-14 Klp2, Date of Completion: 2009