Vázquez-Novelle, María Dolores, Sansregret, Laurent, Dick, Amalie E., Smith, Christopher A., McAinsh, Andrew D., Gerlich, Daniel W. and Petronczki, Mark (2014) Cdk1 inactivation terminates mitotic checkpoint surveillance and stabilizes kinetochore attachments in anaphase. Current Biology, Volume 24 (Number 6). pp. 638-645. doi:10.1016/j.cub.2014.01.034

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Abstract

Two mechanisms safeguard the bipolar attachment of chromosomes in mitosis. A correction mechanism destabilizes erroneous attachments that do not generate tension across sister kinetochores [1]. In response to unattached kinetochores, the mitotic checkpoint delays anaphase onset by inhibiting the anaphase-promoting complex/cyclosome (APC/CCdc20) [2]. Upon satisfaction of both pathways, the APC/CCdc20 elicits the degradation of securin and cyclin B [3]. This liberates separase triggering sister chromatid disjunction and inactivates cyclin-dependent kinase 1 (Cdk1) causing mitotic exit. How eukaryotic cells avoid the engagement of attachment monitoring mechanisms when sister chromatids split and tension is lost at anaphase is poorly understood [4]. Here we show that Cdk1 inactivation disables mitotic checkpoint surveillance at anaphase onset in human cells. Preventing cyclin B1 proteolysis at the time of sister chromatid disjunction destabilizes kinetochore-microtubule attachments and triggers the engagement of the mitotic checkpoint. As a consequence, mitotic checkpoint proteins accumulate at anaphase kinetochores, the APC/CCdc20 is inhibited, and securin reaccumulates. Conversely, acute pharmacological inhibition of Cdk1 abrogates the engagement and maintenance of the mitotic checkpoint upon microtubule depolymerization. We propose that the simultaneous destruction of securin and cyclin B elicited by the APC/CCdc20 couples chromosome segregation to the dissolution of attachment monitoring mechanisms during mitotic exit.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology
Divisions:	Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Cyclin-dependent kinases, Chromosomes, Mitosis, Spindle (Cell division)
Journal or Publication Title:	Current Biology
Publisher:	Cell Press
ISSN:	0960-9822
Official Date:	2014
Dates:	Date Event 2014 Published
Date of first compliant deposit:	26 December 2015
Volume:	Volume 24
Number:	Number 6
Page Range:	pp. 638-645
DOI:	10.1016/j.cub.2014.01.034
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Seventh Framework Programme (European Commission) (FP7), European Research Council (ERC), European Molecular Biology Organization (EMBO), Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung [Swiss National Science Foundation] (SNSF), Fonds zur Förderung der Wissenschaftlichen Forschung (Austria) [Austrian Science Fund] (FWF), Marine Biological Laboratory (Woods Hole, Mass.), Boehringer Ingelheim Fonds, Peter Müller Fellowship, Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Engineering and Physical Sciences Research Council (EPSRC), Fundación Ramón Areces, European Molecular Biology Organization (EMBO), Canadian Institutes of Health Research (CIHR), Cancer Research UK (CRUK)
Grant number:	241548, 258068 (FP7); 281198 (ERC); I021353/1 (BBSRC); EP/F500378/1 (EPSRC)

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