Loss of Kif18A Results in Spindle Assembly Checkpoint Activation at Microtubule-attached Kinetochores

Abstract

The spindle assembly checkpoint (SAC) halts anaphase progression until all kinetochores have obtained bipolar, stable attachments to the mitotic spindle. Upon initial attachment, chromosomes undergo oscillatory movements to reach metaphase. Once a chromosome is correctly attached and positioned, these oscillatory movements are reduced by the motor protein Kif18A, and loss of Kif18A is associated with chromosome hyper-oscillations. By using a haploid genetic approach, we found that loss of Kif18A is lethal in wild-type human HAP1 cells but not in SAC-deficient HAP1 cells. We found that the hyper-oscillations are associated with a loss of tension across kinetochores and SAC-activation but, unexpectedly, not with chromosome missegregations. Strikingly, the SAC-active kinetochores appear to have established fully functional kinetochoremicrotubule (k-Mt) attachments, allowing proper chromosome segregation. These findings shed new light on the role of Kif18A in chromosomal stability and demonstrate that the SAC can be activated by kinetochores that are occupied by fully functional k-Mts that lack tension.

Keywords: Mitosis, Mitotic Checkpoint, Spindle Assembly Checkpoint, Kinetochore, Chromosome Segregation, Kif18A