Proper segregation of the replicated genome requires that kinetochores form and maintain bioriented, amphitelic attachments to microtubules from opposite spindle poles and eliminate erroneous, syntelic attachments to microtubules from the same spindle pole. Phosphorylation of kinetochore proteins destabilizes low-tension kinetochore-microtubule attachments, yet tension stabilizes bioriented attachments. This conundrum for forming high-tension amphitelic attachments is recognized as the “initiation problem of biorientation (IPBO).” A delay before kinetochore-microtubule detachment solves the IPBO, but it lacks a mechanistic framework. We developed a stochastic mathematical model for kinetochore-microtubule error correction in yeast that reveals: (1) under low chromatin tension, requiring a large number of phosphorylation events at multiple sites to achieve detachment provides the necessary delay; and (2) kinetochore-induced microtubule depolymerization generates tension in amphitelic, but not syntelic, attachments. With these requirements, the model provides a mechanistic framework for the delay before detachment to solve the IPBO and demonstrates the high degree of amphitely observed experimentally for wild-type spindles under optimal conditions.
Bibliographical noteFunding Information:
We thank Dr. Yiannis Kaznessis for helpful discussions and Dr. Duncan Clarke, Dr. Melissa Gardner, Dr. Jeremy Chacon, Ms. Aimee Littleton, and Ms. Teahl Banner for technical assistance. This work was supported by the National Institute of General Medical Sciences of the NIH under award numbers R01GM071522 and R01GM076177 to D.J.O. and R01GM064386 to S.B. E.T. was a recipient of a University of Minnesota Interdisciplinary Doctoral Fellowship through the Institute for Advanced Study.
- aurora B kinase
- error correction