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El eje Cdc14B-Cdh1-Plk1 controla el punto de control G2 de respuesta al daño del ADN
Florian Bassermann1, David Frescas, Daniele Guardavaccaro
1Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.
Cell
|July 30, 2008
Resumen
Las células de mamíferos activan una vía de reparación del ADN en la fase G2 después del daño del ADN. Esto involucra a la Cdc14B fosfatasa, lo que lleva a la degradación de Plk1 y la estabilización de las proteínas de punto de control para una respuesta efectiva al daño del ADN G2.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- Genética La genética.
Sus antecedentes:
- Las células de mamíferos requieren mecanismos robustos para evitar la entrada en mitosis después del daño del ADN durante la fase G2.
- El punto de control G2 de la respuesta al daño del ADN (DDR) es crítico para mantener la estabilidad genómica al detener la progresión del ciclo celular.
- Los reguladores clave de la mitosis y el ciclo celular deben controlarse estrictamente para garantizar la reparación adecuada del ADN.
Objetivo del estudio:
- Para dilucidar la vía molecular que rige la respuesta al daño del ADN G2 en las células de mamíferos.
- Identificar el papel de la fosfatasa Cdc14B en la coordinación de la detención del ciclo celular y la reparación del ADN.
- Comprender cómo se regulan las kinasas mitóticas y las proteínas de punto de control durante el estrés genotóxico en G2.
Principales métodos:
- Investigó la localización subcelular y la actividad de Cdc14B en respuesta al estrés genotóxico.
- Se utilizaron ensayos bioquímicos para analizar la activación del complejo/ciclosoma promotor de la anafase (APC/C(Cdh1)).
- Se examinó la degradación de la quinasa mitótica Plk1 y la estabilización de Claspin y Wee1.
- Se evaluó el papel de la enzima deubiquitylating Usp28 en la regulación de la estabilidad de Claspin y la activación de Chk1.
Principales resultados:
- Cdc14B se transloca al nucleoplasma desde el nucleolo tras el estrés genotóxico en G2.
- La activación Cdc14B de APC/C(Cdh1) conduce a la degradación de Plk1, estabilizando Claspin y Wee1 para un punto de control G2 eficiente.
- Usp28 contrarresta la degradación de Claspin mediada por APC/C, asegurando la activación de Chk1 para la reparación del ADN.
Conclusiones:
- Una nueva vía que involucra a Cdc14B, APC/C(Cdh1) y Usp28 es esencial para la respuesta al daño del ADN G2.
- Esta vía asegura la detención del ciclo celular y facilita la reparación del ADN mediante la regulación de proteínas mitóticas y de punto de control clave.
- Los hallazgos proporcionan información crítica sobre el mantenimiento de la integridad genómica después del daño del ADN.
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