Lis1-dynein drives corona compaction and error-correction at kinetochores

Abstract

AbstractMitotic cell division requires that kinetochores form microtubule attachments that can segregate chromosomes and control mitotic progression via the spindle assembly checkpoint. During prometaphase, kinetochores shed a distal domain called the fibrous corona as microtubule attachments form and mature. This shedding is mediated, in part, by the minus-end directed motor dynein, which ‘strips’ kinetochore cargoes along K-fibre microtubules towards the pole. While the main molecular players are well understood, relatively little is known about how dynein stripping is regulated and how it responds to increasing microtubule occupancy. Lis1 is a conserved dynein regulator that associates with kinetochores and is mutated in the severe neurodevelopmental disease lissencephaly. Here, we have combined loss-of-function studies, high-resolution imaging and engineered separation-of-function mutants to define how Lis1 contributes to dynein-mediated corona stripping. We show that cells depleted of Lis1 fail to fully dissemble the corona and delay in metaphase as a result of persistent checkpoint activation. Furthermore, we find that while kinetochore-tethered Lis1-dynein is required for attachment error-correction, the contribution of Lis1 to corona disassembly can be mediated by a rapidly cycling cytosolic pool. These findings support the idea that Lis1 contextualises dynein function at kinetochores to maintain corona disassembly into metaphase and prevent chromosome mis-segregation.