PP2A delays APC/C-dependent degradation of separase-associated but not free securin.
EMBO J
; 33(10): 1134-47, 2014 May 16.
Article
en En
| MEDLINE
| ID: mdl-24781523
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteína Fosfatasa 2
/
Separasa
/
Ciclosoma-Complejo Promotor de la Anafase
/
Securina
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
EMBO J
Año:
2014
Tipo del documento:
Article
País de afiliación:
Alemania