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STIL Microcephaly Mutations Interfere with APC/C-Mediated Degradation and Cause Centriole Amplification

Arquint, Christian and Nigg, Erich A.. (2014) STIL Microcephaly Mutations Interfere with APC/C-Mediated Degradation and Cause Centriole Amplification. Current biology, Vol. 24, H. 4. pp. 351-360.

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Official URL: http://edoc.unibas.ch/dok/A6233691

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Abstract

STIL is a centriole duplication factor that localizes to the procentriolar cartwheel region, and mutations in STIL are associated with autosomal recessive primary microcephaly (MCPH). Excess STIL triggers centriole amplification, raising the question of how STIL levels are regulated.; Using fluorescence time-lapse imaging, we identified a two-step process that culminates in the elimination of STIL at the end of mitosis. First, at nuclear envelope breakdown, Cdk1 triggers the translocation of STIL from centrosomes to the cytoplasm. Subsequently, the cytoplasmic bulk of STIL is degraded via the anaphase-promoting complex/cyclosome (APC/C)-proteasome pathway. We identify a C-terminal KEN box as critical for STIL degradation. Remarkably, this KEN box is deleted in MCPH mutants of STIL, rendering STIL resistant to proteasomal degradation and causing centriole amplification.; Our results reveal a role for Cdk1 in STIL dissociation from centrosomes during early mitosis, with implications for the timing of cartwheel disassembly. Additionally, we propose that centriole amplification triggered by STIL stabilization is the underlying cause of microcephaly in human patients with corresponding STIL mutations.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Cell Biology (Nigg)
UniBasel Contributors:Nigg, Erich A.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Cell Press
ISSN:0960-9822
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Mar 2014 13:13
Deposited On:27 Mar 2014 13:13

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