Unraveling the multifunctionality of human Spindly
type: CreativeWork
description: Spindly was discovered in 2007 as a protein crucial for cells to progress through mitosis. It was shown to be required for recruitment of the dynein/dynactin motor complex to kinetochores thus to promote chromosome alignment and mitotic progression. Kinetochore recruitment of the dynein/dynactin motor complex is crucial for maturation of kinetochore-microtubule attachments and for silencing the spindle assembly checkpoint (SAC), the surveillance pathway that monitors bi-orientation and inhibits anaphase onset until chromosomes are attached to opposing spindle poles. In human cells, Spindly depletion produces strong chromosome alignment defects with cells arrested in mitosis. Conversely expression of a single point mutant form allows for separation of these two functions of Spindly: it rescues chromosome alignment but inhibits SAC silencing and the recruitment of the motor complex. In this work the interaction of Spindly with the dynein/dynactin motor complex was examined, untangling the subunits specifically involved in the binding. It was demonstrated that the single point mutation specifically impairs the interaction with dynactin, potentially affecting the capacity of the motor to strip proteins away and suggesting a role for Spindly as an adaptor of the complex, involved in enhancing its processivity. Previous reports have shown that the constant presence of Spindly at kinetochore impedes SAC inhibition, whereas its depletion allows for an alternative mechanism dynein- independent to silence the SAC on aligned kinetochores. In the present thesis the interaction of Spindly with the proteins involved in the SAC pathway was described, hinting at a further role of Spindly in the SAC signalling related to activation/ maintenance. It has been earlier described that depletion of Drosophila melanogaster Spindly generates defects also in cytoskeletal organisation. Here was identified a pool of human Spindly in interphase cells localising at microtubule plus-ends. It was …
abstract: Spindly was discovered in 2007 as a protein crucial for cells to progress through mitosis. It was shown to be required for recruitment of the dynein/dynactin motor complex to kinetochores thus to promote chromosome alignment and mitotic progression. Kinetochore recruitment of the dynein/dynactin motor complex is crucial for maturation of kinetochore-microtubule attachments and for silencing the spindle assembly checkpoint (SAC), the surveillance pathway that monitors bi-orientation and inhibits anaphase onset until chromosomes are attached to opposing spindle poles. In human cells, Spindly depletion produces strong chromosome alignment defects with cells arrested in mitosis. Conversely expression of a single point mutant form allows for separation of these two functions of Spindly: it rescues chromosome alignment but inhibits SAC silencing and the recruitment of the motor complex. In this work the interaction of Spindly with the dynein/dynactin motor complex was examined, untangling the subunits specifically involved in the binding. It was demonstrated that the single point mutation specifically impairs the interaction with dynactin, potentially affecting the capacity of the motor to strip proteins away and suggesting a role for Spindly as an adaptor of the complex, involved in enhancing its processivity. Previous reports have shown that the constant presence of Spindly at kinetochore impedes SAC inhibition, whereas its depletion allows for an alternative mechanism dynein- independent to silence the SAC on aligned kinetochores. In the present thesis the interaction of Spindly with the proteins involved in the SAC pathway was described, hinting at a further role of Spindly in the SAC signalling related to activation/ maintenance. It has been earlier described that depletion of Drosophila melanogaster Spindly generates defects also in cytoskeletal organisation. Here was identified a pool of human Spindly in interphase cells localising at microtubule plus-ends. It was …
author: Conte, Claudia
language: eng
keywords: Mitosis, Spindly, Cell migration, Dynein/dynactin
date published: 2015
date modified: 2026-07-24T02:08:12Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee