The binding of Borealin to microtubules underlies a tension independent kinetochore-microtubule error correction pathway

Prasad Trivedi,P Todd Stukenberg,Maxim Godzi,Ekaterina L Grishchuk,Anatoly V Zaytsev,Fazly I Ataullakhanov

doi:10.1038/s41467-019-08418-4

Abstract

Proper chromosome segregation depends upon kinetochore phosphorylation by the Chromosome Passenger Complex (CPC). Current models suggest the activity of the CPC decreases in response to the inter-kinetochore stretch that accompanies the formation of bi-oriented microtubule attachments, however little is known about tension-independent CPC phosphoregulation. Microtubule bundles initially lie in close proximity to inner centromeres and become depleted by metaphase. Here we find these microtubules control kinetochore phosphorylation by the CPC in a tension independent manner via a microtubule-binding site on the Borealin subunit. Disruption of Borealin-microtubule interactions generates reduced phosphorylation of prometaphase kinetochores, improper kinetochore-microtubule attachments and weakened spindle checkpoint signals. Experimental and modeling evidence suggests that kinetochore phosphorylation is greatly stimulated when the CPC binds microtubules that lie near the inner centromere, even if kinetochores have high inter-kinetochore stretch. We propose the CPC senses its local environment through microtubule structures to control phosphorylation of kinetochores.

Highlights

Proper chromosome segregation depends upon kinetochore phosphorylation by the Chromosome Passenger Complex (CPC)
CPC recognizes the inner centromere via two distinct histone phosphorylation marks, Histone H3 phosphorylated on T3 (H3pT3)[8,9,10] and Histone H2A phosphorylated on T120 (H2ApT120)[4,8,11,12,13,14]
Apart from tension sensitive mechanisms, the tension-independent mechanisms are likely to be involved since some prometaphase kinetochores may become stretched due to kinetochore localized motor activity on microtubule bundles that lie in close proximity to inner centromeres[33,34]

Summary

Introduction

Proper chromosome segregation depends upon kinetochore phosphorylation by the Chromosome Passenger Complex (CPC). Phosphorylation of kinetochore substrates such as the Ndc[80] complex, by Aurora-B, is higher on unaligned kinetochores than metaphase-aligned kinetochores[15,17], which may regulate many events including the maturation of kinetochoremicrotubule attachments[18] This is caused in part by recruitment of phosphatases to kinetochores after they obtain proper kinetochores attachments[19,20,21], but most models suggest that the CPC’s ability to phosphorylate kinetochores is decreased in metaphase[22,23,24]. Budding yeast and chicken DT40 cells do not require centromere localization for biorientation[28,29,30], but the CPC in yeast require the ability to bind microtubules[28,29] Many of these models suggest that the CPC is regulated by changes to the inner centromeric chromatin that results from the pulling forces exerted by microtubules bound to the kinetochores (inter-kinetochore stretch or centromeric tension)[22,31,32]. Apart from tension sensitive mechanisms, the tension-independent mechanisms are likely to be involved since some prometaphase kinetochores may become stretched due to kinetochore localized motor activity on microtubule bundles that lie in close proximity to inner centromeres[33,34]

Methods

Results

Conclusion