title: Chromatin compaction by condensin I, intra-kinetochore stretch and tension, and anaphase onset, in collective spindle assembly checkpoint interaction.
abstract: The control mechanism in mitosis and meiosis by which cells decide to inhibit or allow segregation, the so-called spindle assembly checkpoint (SAC), increases the fidelity of chromosome segregation. It acts like a clockwork mechanism which measures time in units of stable attachments of microtubules (MTs) to kinetochores (the order parameter). Stable MT-kinetochore attachments mediate poleward forces and 'unstable' attachments, acting alone or together with motor proteins on kinetochores via chromosomes, antipoleward forces. Stable and unstable attachments could be separated, and the non-equilibrium integrated MT mediated force acting on stably attached kinetochores was derived in a collective interaction (Matsson 2009 J. Phys.: Condens. Matter 21 502101), in which kinetochores were treated as rigid protein complexes. As forces and tension in that model became equally distributed in all bioriented sister chromatid (SC) pairs, segregation was inhibited without need of a 'wait-anaphase' signal. In this generalization, the kinetochore is divided into an inner chromatin proximal complex and an outer MT proximal complex, and the integrated MT mediated force is divided into an integrated poleward and an integrated antipoleward force. The model also describes the collective interaction of condensin I with chromatin, which together with the MT mediated dynamics yields the putative in vivo tension in kinetochores and centromeric and pericentromeric chromatin, as a non-linear function of the order parameter. Supported by the compaction force and an increased stiffness in chromatin towards the end of metaphase, the two opposing integrated MT mediated poleward forces, together with metaphase oscillations, induce a swift and synchronized anaphase onset by first increasing the intra-kinetochore stretch. This increase lowers the SAC energy threshold, making a cleavage by separase of all cohesin tethering SC pairs in anaphase energetically possible, thereby reducing the risk for aneuploidy and cancer. It is also shown how this risk might increase in condensin I depleted cells. Moreover, a solution is provided to the fundamental statistical physics problem with a system containing an increasing number of particles (molecular complexes) that become strongly correlated in space.
authors.affiliation: Department of Physics, University of Gothenburg, Göteborg, SE-412 96, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Matsson
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000705:Anaphase / Q000502:physiology*; D000782:Aneuploidy; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D018386:Kinetochores / Q000737:chemistry*; D008540:Meiosis / Q000502:physiology; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D046912:Multiprotein Complexes / Q000378:metabolism*; D008941:Spindle Apparatus / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; C108312:condensin complexes; D000251:Adenosine Triphosphatases