2023
bioRxiv

CENP-E initiates chromosome congression by opposing Aurora kinases to promote end-on microtubule attachments close to centrosomes

Authors:

Kruno Vukušić, Iva M. Tolić

Keywords:

cancer; CENP-E; kinesin-7; mitotic spindle; chromosome congression; Aurora A; Aurora B; chromosome segregation

Abstract:

Chromosome congression to the spindle equator, which recurrently fails in cancer cells leading to aneuploidy, requires the kinetochore motor protein CENP-E/kinesin-7. Current models state that chromosomes congress by CENP-E-driven gliding along spindle microtubules. Here, we show that CENP-E is not essential for the congression movement, but for initiating movement through the formation of end-on attachments. We reached this conclusion by large-scale live-cell imaging under varying activity of CENP-E using lattice light-sheet microscopy. We found that congression without CENP-E is delayed by the activity of centriole-dependent Aurora A and outer-kinetochore-localized Aurora B kinases, which limit the formation of end-on attachments. CENP-E bypasses this inhibition by causing a decrease in Aurora B activity and in phosphorylation of its outer-kinetochore targets. Chromosomally unstable cancer cells rely on CENP-E more than non-cancer cells, leading to segregation errors specifically in cancer cells with prolonged mitosis, thereby exposing a mitotic timing-dependent vulnerability of cancer cells.