MPS1 regulation at the kinetochore: How is the mitotic Spindle Assembly Checkpoint initiated and silenced?

Speaker Dr Daniel Hayward, King’s Prize Fellow and Professor Anthony Mellows Medal Receipiant, The Randall

Title MPS1 regulation at the kinetochore: How is the mitotic Spindle Assembly Checkpoint initiated and silenced?

Host Jody Rosenblat

 

Abstract The spindle assembly checkpoint protects genome stability in mitosis by preventing chromosome segregation until incorrect microtubule-kinetochore attachment geometries have been eliminated, and chromosome biorientation has been completed. These error correction and checkpoint processes are linked by the conserved Aurora B and MPS1 kinases. MPS1-dependent checkpoint signaling is believed to be initiated by kinetochores without microtubule attachments, including those generated by Aurora B-mediated error correction. The current model posits that MPS1 competes with microtubules for binding sites at the kinetochore. MPS1 is thought to first recognize kinetochores not blocked by microtubules, then initiate checkpoint signaling. However, MPS1 is also required for correction of microtubule-kinetochore attachments errors. This function, which must require direct interaction with microtubule-attached kinetochores, is not readily explained by the current model. We show that MPS1 transiently localizes to end-on attached kinetochores, and that this recruitment depends on the relative activities of Aurora B and its counteracting phosphatase PP2A-B56 rather than microtubule-attachment state per se. At attached kinetochores, MPS1 actively promotes microtubule release together with Aurora B. Furthermore, MPS1 is detected at attached kinetochores before the removal of microtubules. During chromosome alignment, MPS1 therefore coordinates both the resolution of incorrect microtubule-kinetochore attachments and the initiation of spindle checkpoint signaling.