Efficient mitotic checkpoint signaling depends on integrated activities of Bub1 and the RZZ complex

TY - JOUR

T1 - Efficient mitotic checkpoint signaling depends on integrated activities of Bub1 and the RZZ complex

AU - Zhang, Gang

AU - Kruse, Thomas

AU - Guasch Boldú, Claudia

AU - Garvanska, Dimitriya H

AU - Coscia, Fabian

AU - Mann, Matthias

AU - Barisic, Marin

AU - Nilsson, Jakob

N1 - © 2019 The Authors.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Kinetochore localized Mad1 is essential for generating a "wait anaphase" signal during mitosis, hereby ensuring accurate chromosome segregation. Inconsistent models for the function and quantitative contribution of the two mammalian Mad1 kinetochore receptors: Bub1 and the Rod-Zw10-Zwilch (RZZ) complex exist. By combining genome editing and RNAi, we achieve penetrant removal of Bub1 and Rod in human cells, which reveals that efficient checkpoint signaling depends on the integrated activities of these proteins. Rod removal reduces the proximity of Bub1 and Mad1, and we can bypass the requirement for Rod by tethering Mad1 to kinetochores or increasing the strength of the Bub1-Mad1 interaction. We find that Bub1 has checkpoint functions independent of Mad1 localization that are supported by low levels of Bub1 suggesting a catalytic function. In conclusion, our results support an integrated model for the Mad1 receptors in which the primary role of RZZ is to localize Mad1 at kinetochores to generate the Mad1-Bub1 complex.

AB - Kinetochore localized Mad1 is essential for generating a "wait anaphase" signal during mitosis, hereby ensuring accurate chromosome segregation. Inconsistent models for the function and quantitative contribution of the two mammalian Mad1 kinetochore receptors: Bub1 and the Rod-Zw10-Zwilch (RZZ) complex exist. By combining genome editing and RNAi, we achieve penetrant removal of Bub1 and Rod in human cells, which reveals that efficient checkpoint signaling depends on the integrated activities of these proteins. Rod removal reduces the proximity of Bub1 and Mad1, and we can bypass the requirement for Rod by tethering Mad1 to kinetochores or increasing the strength of the Bub1-Mad1 interaction. We find that Bub1 has checkpoint functions independent of Mad1 localization that are supported by low levels of Bub1 suggesting a catalytic function. In conclusion, our results support an integrated model for the Mad1 receptors in which the primary role of RZZ is to localize Mad1 at kinetochores to generate the Mad1-Bub1 complex.

U2 - 10.15252/embj.2018100977

DO - 10.15252/embj.2018100977

M3 - Journal article

C2 - 30782962

SN - 0261-4189

VL - 38

JO - E M B O Journal

JF - E M B O Journal

IS - 7

M1 - e100977

ER -