Publication Date:
2014-11-11
Description:
The spindle assembly checkpoint (SAC) maintains genomic stability by delaying chromosome segregation until the last chromosome has attached to the mitotic spindle. The SAC prevents the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase from recognizing cyclin B and securin by catalysing the incorporation of the APC/C co-activator, CDC20, into a complex called the mitotic checkpoint complex (MCC). The SAC works through unattached kinetochores generating a diffusible 'wait anaphase' signal that inhibits the APC/C in the cytoplasm, but the nature of this signal remains a key unsolved problem. Moreover, the SAC and the APC/C are highly responsive to each other: the APC/C quickly targets cyclin B and securin once all the chromosomes attach in metaphase, but is rapidly inhibited should kinetochore attachment be perturbed. How this is achieved is also unknown. Here, we show that the MCC can inhibit a second CDC20 that has already bound and activated the APC/C. We show how the MCC inhibits active APC/C and that this is essential for the SAC. Moreover, this mechanism can prevent anaphase in the absence of kinetochore signalling. Thus, we propose that the diffusible 'wait anaphase' signal could be the MCC itself, and explain how reactivating the SAC can rapidly inhibit active APC/C.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312099/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312099/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Izawa, Daisuke -- Pines, Jonathon -- 092096/Wellcome Trust/United Kingdom -- 13959/Cancer Research UK/United Kingdom -- A13678/Cancer Research UK/United Kingdom -- A13959/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2015 Jan 29;517(7536):631-4. doi: 10.1038/nature13911. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Gurdon Institute and Department of Zoology, Tennis Court Road, Cambridge CB2 1QN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383541" target="_blank"〉PubMed〈/a〉
Keywords:
Anaphase
;
Anaphase-Promoting Complex-Cyclosome/*antagonists & inhibitors/metabolism
;
Animals
;
Cdc20 Proteins/*metabolism
;
Cytoplasm/enzymology/metabolism
;
HeLa Cells
;
Humans
;
M Phase Cell Cycle Checkpoints
;
*Mitosis
;
Multiprotein Complexes/*metabolism
;
Protein Binding
;
Protein Structure, Tertiary
;
Protein-Serine-Threonine Kinases/chemistry/metabolism
;
Spindle Apparatus/metabolism
;
Substrate Specificity
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
