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  PP2A delays APC/C-dependent degradation of separase-associated but not free securin

Hellmuth, S., Böttger, F., Pan, C., Mann, M., & Stemmann, O. (2014). PP2A delays APC/C-dependent degradation of separase-associated but not free securin. EMBO JOURNAL, 33(10), 1134-1147. doi:10.1002/embj.201488098.

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 Creators:
Hellmuth, Susanne1, Author
Böttger, Franziska1, Author
Pan, Cuiping2, Author              
Mann, Matthias2, Author              
Stemmann, Olaf1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: ANAPHASE-PROMOTING COMPLEX/CYCLOSOME; SISTER-CHROMATID DISJUNCTION; PROTEIN PHOSPHATASE 2A; SUBSTRATE DEGRADATION; UBIQUITIN LIGASE; COHESIN CLEAVAGE; DNA-DAMAGE; CELL-CYCLE; INHIBITION; MITOSISAPC/C; PP2A; securin; separase; ubiquitylation;
 Abstract: The universal triggering event of eukaryotic chromosome segregation is cleavage of centromeric cohesin by separase. Prior to anaphase, most separase is kept inactive by association with securin. Protein phosphatase 2A (PP2A) constitutes another binding partner of human separase, but the functional relevance of this interaction has remained enigmatic. We demonstrate that PP2A stabilizes separase-associated securin by dephosphorylation, while phosphorylation of free securin enhances its polyubiquitylation by the ubiquitin ligase APC/C and proteasomal degradation. Changing PP2A substrate phosphorylation sites to alanines slows degradation of free securin, delays separase activation, lengthens early anaphase, and results in anaphase bridges and DNA damage. In contrast, separase-associated securin is destabilized by introduction of phosphorylation-mimetic aspartates or extinction of separase-associated PP2A activity. G2- or prometaphase-arrested cells suffer from unscheduled activation of separase when endogenous securin is replaced by aspartate-mutant securin. Thus, PP2A-dependent stabilization of separase-associated securin prevents precocious activation of separase during checkpoint-mediated arrests with basal APC/C activity and increases the abruptness and fidelity of sister chromatid separation in anaphase.

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Language(s): eng - English
 Dates: 2014
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000336495900006
DOI: 10.1002/embj.201488098
 Degree: -

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Title: EMBO JOURNAL
Source Genre: Journal
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Publ. Info: 111 RIVER ST, HOBOKEN 07030-5774, NJ USA : WILEY-BLACKWELL
Pages: - Volume / Issue: 33 (10) Sequence Number: - Start / End Page: 1134 - 1147 Identifier: ISSN: 0261-4189