53BP1 and USP28 mediate p53 activation and G1 arrest after centrosome loss or extended mitotic duration.
J Cell Biol
; 214(2): 155-66, 2016 07 18.
Article
em En
| MEDLINE
| ID: mdl-27432897
ABSTRACT
In normal human cells, centrosome loss induced by centrinone-a specific centrosome duplication inhibitor-leads to irreversible, p53-dependent G1 arrest by an unknown mechanism. A genome-wide CRISPR/Cas9 screen for centrinone resistance identified genes encoding the p53-binding protein 53BP1, the deubiquitinase USP28, and the ubiquitin ligase TRIM37. Deletion of TP53BP1, USP28, or TRIM37 prevented p53 elevation in response to centrosome loss but did not affect cytokinesis failure-induced arrest or p53 elevation after doxorubicin-induced DNA damage. Deletion of TP53BP1 and USP28, but not TRIM37, prevented growth arrest in response to prolonged mitotic duration. TRIM37 knockout cells formed ectopic centrosomal-component foci that suppressed mitotic defects associated with centrosome loss. TP53BP1 and USP28 knockouts exhibited compromised proliferation after centrosome removal, suggesting that centrosome-independent proliferation is not conferred solely by the inability to sense centrosome loss. Thus, analysis of centrinone resistance identified a 53BP1-USP28 module as critical for communicating mitotic challenges to the p53 circuit and TRIM37 as an enforcer of the singularity of centrosome assembly.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
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Centrossomo
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Ubiquitina Tiolesterase
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Pontos de Checagem da Fase G1 do Ciclo Celular
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Proteína 1 de Ligação à Proteína Supressora de Tumor p53
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Mitose
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article