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El procesamiento mediado por proteasomas de Def1, un paso crítico en la respuesta celular al estrés de la
Marcus D Wilson1, Michelle Harreman1, Michael Taschner1
1Mechanisms of Transcription Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute, South Mimms EN6 3LD, UK.
Cell
|September 3, 2013
Resumen
El daño en el ADN desencadena la degradación de la ARN polimerasa II (RNAPII) a través de Def1. Def1 se activa mediante el procesamiento, lo que lleva a la acumulación nuclear y el reclutamiento de la ligasa E3 para la poliubiquitilación de RNAPII y la descomposición proteasómica.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
- Genética La genética.
Sus antecedentes:
- El daño en el ADN activa una proteína.
- Mecanismo de último recurso.
- que implica la poliubiquitilación y la degradación de la subunidad más grande de la ARN polimerasa II (RNAPII).
- En la levadura, este proceso se basa en la proteína Def1, pero el mecanismo preciso sigue sin estar claro.
Objetivo del estudio:
- Para dilucidar el mecanismo previamente no resuelto por el cual Def1 facilita la degradación de RNAPII durante el estrés de transcripción.
- Para detallar la activación y función de Def1 en respuesta al daño del ADN.
Principales métodos:
- Investigó la activación de Def1 a través de la ubicuidad y el procesamiento dependiente del proteasoma.
- Se analizó la localización y la interacción de Def1 procesado con RNAPII.
- Caracterizó el reclutamiento del complejo de ligasa Elongin-Cullin E3 por Def1.1.
Principales resultados:
- La activación de Def1 implica ubicuidad y procesamiento dependiente del proteasoma, eliminando un dominio de localización citoplasmático.
- El Def1 procesado se acumula en el núcleo y se une al RNAPII.
- Def1 utiliza su dominio de unión a la ubiquitina para reclutar el complejo de ligasa Elongin-Cullin E3 a través de Ela1, facilitando la poliubiquitilación de Rpb1.
Conclusiones:
- Def1 actúa como un facilitador crucial para la actividad de la ubiquitina ligasa de Elongin-Cullin en respuesta al estrés de transcripción.
- Se ha descrito un mecanismo de varios pasos para la poliubiquitilación y degradación de Rpb1, mediada por Def1.
- El procesamiento de Def1 es esencial para su localización nuclear y posterior función en el desencadenamiento de la degradación de RNAPII.
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