MPS1 localizes to end-on microtubule-attached kinetochores to promote microtubule release

TY - JOUR

T1 - MPS1 localizes to end-on microtubule-attached kinetochores to promote microtubule release

AU - Hayward, Daniel

AU - Roberts, Emile

AU - Gruneberg, Ulrike

N1 - Funding Information: We thank Francis Barr for encouragement, advice, and discussions and Bela Novak and Tomoaki Sobajima for their helpful comments on the manuscript. This work was funded by a Cancer Research UK Discovery Programme grant DRCNPG-Nov21\100004 to U.G., a Medical Research Council grant MR/K006703/1 to U.G., an Edward Penley Abraham grant RF 280 to U.G., and a Medical Research Council studentship to E.R. The authors acknowledge that this work would not have been possible without the HeLa cell line, which was developed from Henrietta Lacks’ cells taken without compensation or informed consent. Publisher Copyright: © 2022 The Author(s)

PY - 2022/12/5

Y1 - 2022/12/5

N2 - In eukaryotes, 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 Ser/Thr kinases.1,2 MPS1-dependent checkpoint signaling is believed to be initiated by kinetochores without end-on microtubule attachments,3,4 including those generated by Aurora B-mediated error correction. The current model posits that MPS1 competes with microtubules for binding sites at the kinetochore.3,4 MPS1 is thought to first recognize kinetochores not blocked by microtubules and then initiate checkpoint signaling. However, MPS1 is also required for chromosome biorientation and correction of microtubule-kinetochore attachment errors.5,6,7,8,9 This latter function, which must require direct interaction with microtubule-attached kinetochores, is not readily explained within the constraints of the current model. Here, 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. MPS1 autophosphorylation also regulates MPS1 kinetochore levels but does not determine the response to microtubule attachment. At end-on attached kinetochores, MPS1 actively promotes microtubule release together with Aurora B. Furthermore, in live cells, 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.

AB - In eukaryotes, 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 Ser/Thr kinases.1,2 MPS1-dependent checkpoint signaling is believed to be initiated by kinetochores without end-on microtubule attachments,3,4 including those generated by Aurora B-mediated error correction. The current model posits that MPS1 competes with microtubules for binding sites at the kinetochore.3,4 MPS1 is thought to first recognize kinetochores not blocked by microtubules and then initiate checkpoint signaling. However, MPS1 is also required for chromosome biorientation and correction of microtubule-kinetochore attachment errors.5,6,7,8,9 This latter function, which must require direct interaction with microtubule-attached kinetochores, is not readily explained within the constraints of the current model. Here, 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. MPS1 autophosphorylation also regulates MPS1 kinetochore levels but does not determine the response to microtubule attachment. At end-on attached kinetochores, MPS1 actively promotes microtubule release together with Aurora B. Furthermore, in live cells, 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.

UR - http://www.scopus.com/inward/record.url?scp=85143277808&partnerID=8YFLogxK

U2 - 10.1016/j.cub.2022.10.047

DO - 10.1016/j.cub.2022.10.047

M3 - Article

C2 - 36395767

SN - 0960-9822

VL - 32

SP - 5200-5208.e8

JO - Current biology : CB

JF - Current biology : CB

IS - 23

ER -